JP5926724B2 - How to treat cancer - Google Patents

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JP5926724B2
JP5926724B2 JP2013502699A JP2013502699A JP5926724B2 JP 5926724 B2 JP5926724 B2 JP 5926724B2 JP 2013502699 A JP2013502699 A JP 2013502699A JP 2013502699 A JP2013502699 A JP 2013502699A JP 5926724 B2 JP5926724 B2 JP 5926724B2
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JP2013523744A (en
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ニール ピー. デサイ,
ニール ピー. デサイ,
パトリック スーン−シオン,
パトリック スーン−シオン,
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アブラクシス バイオサイエンス, エルエルシー
アブラクシス バイオサイエンス, エルエルシー
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Description

Cross-reference to related applications This application is directed to US Provisional Patent Application 61 / 318,774, filed March 29, 2010, and 61 / 433,132, filed January 14, 2011. The contents of each of the above-mentioned US provisional patent applications are hereby incorporated by reference in their entirety.

TECHNICAL FIELD The present invention relates to methods and compositions for treating non-small cell lung cancer (NSCLC) by administering a composition comprising nanoparticles comprising paclitaxel and albumin and a platinum-based agent (eg, carboplatin). Related to things.

  In the United States, lung cancer is the leading cause of cancer deaths in both men and women. In 1998, an estimated 171500 new cases were diagnosed and approximately 160,100 deaths occurred as a result of lung cancer. More women die from lung cancer and four times more men die from lung cancer than the combined number of women who die from breast cancer, ovarian cancer, and uterine cancer. Most patients diagnosed with NSCLC cannot be cured by surgery and eventually die from NSCLC. See SEER Cancer Statistics Review, 2001. The median survival of patients who have not been treated with metastatic NSCLC is only 4-5 months, and the survival rate after 1 year is only 10 percent (Non-Patent Document 1).

  Chemotherapy only improves the median survival (MST) of patients with locally advanced or metastatic NSCLC compared to best supportive care (BSC). . First generation chemotherapeutic agents prolonged survival of patients with stage IIIB and stage IV NSCLC by 10% to 15% when compared to BSC. Multiple meta-analysis shows that regimens containing cisplatin extend MST for 6-8 weeks and increase survival after 15 years from 15% to 25%. See Non-Patent Document 2; Non-Patent Document 3; Non-Patent Document 4. The most commonly used drugs for treating NSCLC include carboplatin (response rate (RR): 20% to 25%; see Non-Patent Document 5), Taxol® ( RR: 20% to 25%; see non-patent document 6; see non-patent document 7), docetaxel (RR: 23% to 33%; see non-patent document 8; see non-patent document 9), gemcitabine ( RR: 20% to 25%; Non-Patent Document 10; Sorensen JB Lung Cancer. 1995; Vol. 12 (Special Issue 1): see pages S173 to S175), and vinorelbine (RR: 29.4) %; See Depierre A. et al., Proc ASCO, 1988, 7: 201). The MST with these drugs varies between 7.5 and 9.5 months.

Most current treatment combinations center around the use of platinum-based regimens. Platinum-based agents are alkylating agents that covalently bind to DNA and crosslink DNA strands, resulting in inhibition of DNA synthesis and function, as well as transcription. The combination of platinum-based chemotherapy showed an improvement over monotherapy in advanced NSCLC. Duvey S. And Schiller J. et al. H. Hematol Oncol Clin N Am. 2004, 18: 101-114. For example, Taxol® (about 200-225 mg / m 2 ) in combination with carboplatin (AUC = 6) administered at q3w is a commonly used and well tolerated treatment regimen for NSCLC patients. Yes, in phase III trials it has resulted in 17%, 25%, 29%, 32% and 37% objective responses. Schiller J.M. H. Et al., N Engl J Med. 2002; 346: 92-98; Kelly K.M. Et al., J Clin Oncol. 2001; 19: 3210-3218; Herbst R .; S. Et al., J Clin Oncol. 2004; 22: 785-794; Scagliotti G. et al. V. Et al., J Clin Oncol. 2002; 20: 4285-4291; Lilenbaum R .; C. Et al., American Society of Clinical Oncology (ASCO), June 2002, abstract 2 pages. The toxicity associated with this regimen was similar in nature to that associated with Taxol® and carboplatin, respectively, and this combination showed no new or unexpected toxicity. Efficacy parameters were about 100 mg / m 2 Taxol® once per week with AUC = 6 carboplatin for 3 out of 4 weeks and 100 mg on the first day of each 3 week cycle. Similar to / m 2 Taxol® and AUC = 6 carboplatin. Belani et al., J Clin Oncol. 2008; 26 (3): 468-473.

  Carboplatin / Taxol® is compared with other doublets (cisplatin / Taxol® vs. cisplatin / gemcitabine vs. cisplatin / docetaxel vs. carboplatin / Taxol®) Recent Phase III Tests have shown that all combinations show similar effectiveness. Schiller J.M. H. Et al., N Engl J Med. 2002; 346: 92-98. However, because of its more favorable safety profile, the Eastern Collaborative Oncology Group (ECOG) has chosen carboplatin / Taxol® as its reference regimen for future studies. Schiller J.M. H. Et al., N Engl J Med. 2002; 346: 92-98.

  Taxol® (Bristol-Myers Squibb Co., Princeton, New Jersey) contains paclitaxel, an active agent for chemotherapy. Paclitaxel binds to the β-subunit of tubulin, which is a component of microtubules, and causes ultrastabilization of the microtubule structure. The resulting paclitaxel / microtubule structure cannot be disassembled, which stops mitosis and inhibits angiogenesis. Because paclitaxel is highly hydrophobic, commercial formulations include synthetic solvents that allow parenteral administration: Taxol® is a Cremophor® EL (polyethylated castor oil (polyethylated). castor oil)) and ethanol are included as paclitaxel vehicle.

  The solvent used in Taxol® raises serious concerns due to its inherent negative properties. New data indicate that Cremophor is a biologically and pharmacologically active compound that directly contributes to the severe toxicity observed in patients treated with Taxol®. Well-characterized, solvent-related toxicities include severe hypersensitivity reactions (which can be fatal even with steroid premedication), histamine release, and demyelination and axonal degeneration Long term, possibly irreversible, peripheral neuropathy. Gelderblom H.C. Et al., Eur J Cancer. 2001; 37: 1590-8, review; Lorenz W. Agents and Actions, 1977; 7: 63-67; Weiss R., et al. B. Et al., J Clin Oncol. 1990; 8: 1263-1268. Furthermore, these solubilizers also have a detrimental effect on efficacy due to the encapsulation of the active drug in micelles formed in the plasma compartment. ten Tige A.M. J. et al. Et al., Clin Pharmacokinet. 2003; 42: 665-85, see review. Such encapsulation alters drug pharmacokinetics (PK), greatly increases drug exposure throughout the body, decreases drug clearance, renders PK non-linear, and eliminates dose-dependent anti-tumor activity Let ten Tige A.M. J. et al. Et al., Clin Pharmacokinet. 2003; 42: 665-85, review; Et al., Proceedings of ASCO, 1998, 17 volumes, abstract 388; Et al., Cancer Res. 1999; 59 (7): 1454-1457; van Tellingen O., et al. Et al., Br J Cancer. 1999; 81: 330-5. Drug encapsulation affects not only the taxane, but also co-administered drugs (eg, anthracyclines, platinum compounds) and is therefore an important consideration when designing combination therapy. ten Tige A.M. J. et al. Et al., Clin Pharmacokinet. 2003; 42: 665-85, see review.

  New data indicate that the solvent used in Taxol® may negatively affect the efficacy and toxicity profile of chemotherapy containing Taxol®, so new paclitaxel formulations Things are being developed. Nab-paclitaxel (ABI-007 or Abraxane <(R)>, Abraxis BioScience, Los Angeles, California) is a new, solvent-free, non-crystalline, suspended in normal saline Amorphous, albumin-bound paclitaxel particles (having an average size of about 130 nm). See, for example, U.S. Patent Nos. 5,916,596; 6,506,405; 6,749,868; 6,537,579; and 7,820,788. See also US Patent Application Publication No. 2007/0082838. Nab-paclitaxel is the first of a new class of anticancer drugs that incorporates the particle method and takes advantage of the unique properties of albumin, the natural carrier of lipophilic molecules in humans. . Nab-paclitaxel uses the albumin receptor (gp60) / caveolin-1 (CAV1) pathway to achieve a high intratumoral accumulation of paclitaxel. See Desai et al., Clin Cancer Res, 2006; 12 (4): 1317-1324. Nab-paclitaxel is advantageous compared to Taxol® in reducing toxicity, increasing ease of administration, reducing drug infusion time, and avoiding hypersensitivity reactions.

Nab-paclitaxel was administered as a first-line therapy to 43 NSCLC patients at a dose of 260 mg / m 2 every 3 weeks, resulting in an objective response rate of 16% and an additional 49% Who have achieved disease control (defined as an objective response in addition to disease stability for at least 16 weeks), are well tolerated, and develop any grade 4 toxicity at any point in the treatment period I couldn't see it. Green M.M. R. Et al., Ann Oncol. 2006; 17: 1263-8. Nab-paclitaxel was given at a dose of 125 mg / m 2 once a week for 3 weeks to 40 elderly patients with stage IV NSCLC (median age 70 years) for 1 week Upon withdrawal, the objective response rate and disease control rate were 30% and 50%, respectively. Rizvi N.R. A. Et al., J Clin Oncol. See 2006 ASCO Annual Meeting Proceedings (Edited after the General Meeting), Volume 24, page 18S (June 20 issue), 2006: 7105.

  In phase III trials, the high response rate due to monotherapy does not necessarily translate into a significantly higher response rate due to combination therapy, nor does it result in further efficacy. Lynch et al., J Clin Oncol. 2010; 28 (6): 911-1117 (“Many Phase III trials are exploring targeting methods in combination with platinum dual therapy but have not been successful”). I want.

Aiming for an improved objective response rate compared to Taxol®, Nab-paclitaxel was combined with carboplatin to evaluate efficacy and toxicity in NSCLC. Every 100 weeks, 100 patients treated with carboplatin (AUC6) plus Nab-paclitaxel at a dose of 225-340 mg / m 2 had an overall response rate of 27% (Hawkins MJ et al., J Clin Oncol., 2006 ASCO Annual Meeting Proceedings (Edited after the General Meeting), 24, 18S (June 20th issue, 2006: 7132), NSCLC patients with carboplatin In combination, 50% response rate was reported when Nab-paclitaxel was used once a week at 100 mg / m 2 (Allerton JP et al., J Clin Oncol., 2006 ASCO Annual Meeting Proceedings (Edited after the general meeting), Volume 24, page 18S (Special Issue on June 20th), 2006: 7127 See). In another study, NSCLC patients with adenocarcinoma confirmed histologically and given Nab-paclitaxel once weekly in combination with carboplatin achieved 59% ORR, whereas squamous epithelium. NSCLC patients with histologically confirmed cell cancer achieved 39% ORR. Socinski M.M. A. Et al., IASLC, 13th World Lung Cancer Convention, San Francisco, CA; July 31-August 4, 2009.

  NSCLC is also gaining further data that treatment and survival results are diverse cancers that often depend on the histological characteristics of the malignancy and the molecular profile of NSCLC. For example, survival analysis has already shown that interstitial SPARC (also known as osteonectin and BM40) is significantly associated with hypoxia / acidity markers and poor prognosis in non-small cell lung cancer Show. Koukuurakis et al., Cancer Research. 2003, 63: 53756-5380. In addition, previous studies have also shown that histological characteristics can be an important predictor of clinical response. For example, in a NSCLC Phase III trial comparing cisplatin and gemcitabine with cisplatin and pemetrexed, cisplatin and pemetrexed were significantly better than cisplatin and gemcitabine therapy in patients with adenocarcinoma and large cell carcinoma Survival was obtained as a result, whereas no significant difference was observed in squamous cell carcinoma. Scagliotti et al., J Clin Oncol. 2008; 26 (21) 3543-3551. Squamous cell carcinoma of the lung accounts for one third of primary lung cancer and common malignant tumors with poor prognosis. In squamous cell carcinoma, stage progression and poor prognosis are correlated with increased caveolin-1 expression (Yoo et al., Lung Cancer. 2003, 42: 195-202).

  Continuous assessment of new approaches to treat NSCLC is essential to increase the survival rate and quality of life of NSCLC patients.

  The disclosures of all publications, patents, patent applications, and patent application publications mentioned in this specification are hereby incorporated by reference in their entirety. This application also incorporates US Provisional Patent Application No. 61 / 318,777 in its entirety by reference.

Rapp E.I. Et al., J Clin Oncol. 1988; 6: 633-41 Non Small Cell Lung Cancer Collaborative Group. Br Med J.M. 1995; 311: 899-909. Grili R. Et al., J Clin Oncol. 1993; 11: 1866-1872. Soupet P.M. J. et al. Et al., Lancet, 1993; 342: 19-21. Bonomi P.M. D. Et al., J Clin Oncol. 1989; 7: 1602-13 Gatzemeier U. Et al., Lung Cancer. 1995; Volume 12 (Special Issue 2): S101 to S106 Hainsworth J.H. D. Et al., J Clin Oncol, 1995, 13 (7): 1609-1614. Fossella F.E. V. Et al., J Clin Oncol. 1995; 13 (3): 645-651 Cerny T. Et al., Br J Cancer. 1994; 70: 384-387. Shepherd F.M. A. Anticancer Drugs. 1995; Volume 6 (No. 6): 9-25 pages

  As used herein, a method of treating non-small cell lung cancer (NSCLC) in an individual in need thereof, comprising: (a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin (herein) The method is also provided comprising the steps of: (b) also administering an effective amount of a platinum-based agent, also referred to hereinafter as a “nanoparticle composition” or “paclitaxel nanoparticle composition”.

  In some embodiments, the NSCLC is squamous cell carcinoma (ie epidermoid carcinoma), large cell carcinoma, adenocarcinoma, adenosquamous carcinoma, polymorphic element, sarcoma-like element, or sarcoma Cancer with components, carcinoid tumor, or salivary gland cancer. In some embodiments, the NSCLC is a squamous cell cancer. In some embodiments, the NSCLC is a latent tumor, stage 0 tumor, stage I tumor, stage II tumor, stage IIIA tumor, stage IIIB tumor, or stage IV tumor. is there. In some embodiments, the NSCLC is early NSCLC, non-metastatic NSCLC, primary NSCLC, advanced NSCLC, locally advanced NSCLC, metastatic NSCLC, remission NSCLC, or recurrent NSCLC. In some embodiments, the NSCLC is resectable local NSCLC, unresectable local NSCLC, or unresectable NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC, PS0-1 and FEV 1> 800 ml. In some embodiments, the method is a method of treating NSCLC as first line therapy or second line therapy. In some embodiments, the individual being treated is ineligible for VEGF directed therapy, eg, ineligible for treatment with bevacizumab. In some embodiments, the individual is at risk of bleeding from VEGF directed therapy.

In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (eg, 50 mg / m 2 , 75 mg / m 2 , or 100 mg / m 2 ). And an effective amount of a platinum-based drug is about AUC = 2 to about AUC = 6 (eg, AUC = 3, AUC = 4.5, or AUC = 6). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week, and an effective amount of a platinum-based agent is administered once every three weeks. In some embodiments, the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (administered once a week) and the effective amount of the platinum-based agent is about AUC = 2 to about AUC = 6 (once administered every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 100 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 6 ( Once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 75 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 4. 5 (once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 3 ( Once every 3 weeks). In some embodiments, the paclitaxel nanoparticle composition and / or the platinum-based agent is administered intravenously. In some embodiments, the paclitaxel nanoparticle composition and the platinum-based agent are administered intravenously.

  In some embodiments, the albumin is human serum albumin. In some embodiments, the nanoparticle comprises paclitaxel coated with albumin. In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is about 200 nm or less (such as less than about 200 nm). In some embodiments, the composition comprises an albumin stabilized nanoparticulate formulation of paclitaxel (Nab-paclitaxel (Abraxane®)). In some embodiments, the composition is Nab-paclitaxel (Abraxane®).

  In some embodiments, the platinum-based agent covalently binds to DNA, crosslinks, inhibits DNA synthesis, and / or inhibits transcripts. In some embodiments, the platinum-based agent is carboplatin, cisplatin, or oxaliplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin.

  In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered sequentially, co-administered, or co-administered.

  The methods described herein have the following objectives: alleviating one or more symptoms of NSCLC, delaying the progression of NSCLC, reducing tumor size in NSCLC patients, Inhibiting, prolonging overall survival, prolonging progression-free survival, preventing or delaying tumor metastasis due to NSCLC, reducing (eg eradicating) tumor metastasis due to existing NSCLC, existing It can be used for any one or more of reducing the occurrence or burden of tumor metastasis due to NSCLC, or preventing recurrence of NSCLC.

Thus, for example, the present invention provides a method of treating NSCLC in an individual in need thereof, comprising: (a) an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin; and (b) an effective amount. An effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 100 mg / m 2 (administered once a week) and an effective amount of carboplatin is AUC = 6 (3 weeks Are administered once per time).

Accordingly, the present invention also provides a method of treating advanced NSCLC in an individual in need thereof, comprising: (a) an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin; and (b) an effective amount. An effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin as a first-line drug is 100 mg / m 2 (administered once a week) An effective amount of carboplatin is provided, wherein AUC = 6 (administered once every 3 weeks).

  Accordingly, there is also a method for treating NSCLC in an individual in need thereof, comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum-based agent. Also provided is a method comprising the step of administering, wherein the NSCLC is squamous cell carcinoma.

  In some embodiments, a method of treating NSCLC in an individual in need thereof comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum base. A method is provided wherein the individual being treated is ineligible for VEGF directed therapy, eg, ineligible for treatment with bevacizumab. In some embodiments, the individual is at risk of bleeding from VEGF directed therapy.

Also described herein is a method of treating NSCLC in an individual (eg, a human) comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum-based Administering an agent and c) radiation (eg, chest radiation), wherein an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is from 20 mg / m 2 to about 60 mg / m 2 (eg, , 40 mg / m 2 ) (administered once a week) and an effective amount of a platinum-based drug is about AUC = 2 to about AUC = 6 (eg, AUC = 2) (administered once a week) Also provided is a method in which the synchronic chest radiation is about 25 to about 40 divisions (eg, about 33 divisions) via 3D conformal methods or intensity modulation methods. In some embodiments, a method of treating NSCLC in an individual (eg, a human) comprises: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum-based agent. And c) administering radiation (eg, chest radiation), wherein an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is 20 mg / m 2 to about 60 mg / m 2 (eg, 40 mg / m 2 ) (administered once a week), an effective amount of a platinum-based drug is about AUC = 2 to about AUC = 6 (eg, AUC = 2) (administered once a week), and The method wherein the synchronic chest radiation is from about 25 to about 40 divisions (eg, about 33 divisions) via 3D conformal or intensity modulation methods further comprises consolidation therapy, wherein The therapy comprises administering to an individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin and b) an effective amount of a platinum-based agent, wherein the nanoparticles comprising paclitaxel and albumin An effective amount of a composition comprising about 50 to about 125 mg / m 2 (eg, 50 mg / m 2 , 75 mg / m 2 , or 100 mg / m 2 ) (administered once a week), and an effective amount of carboplatin is About AUC = 2 to about AUC = 6 (eg, AUC = 3, AUC = 4.5, or AUC = 6) (administered once every 3 weeks). In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC, PS0-1 and FEV 1> 800 ml. In some embodiments, the platinum-based agent is carboplatin.

  A method of treating NSCLC in an individual comprising the steps of: a) administering an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum-based agent, , (I) squamous cell carcinoma, (ii) differential levels of caveolin-1 (CAV1), (iii) differential levels of SPARC, (iv) differential levels of hypoxia markers, (v) tumor acidity Degree difference, (vi) difference in level of gp60, (vii) difference in level of thymidylate synthase (TS), (viii) difference in level of S phase kinase related protein (Skp2), (ix) single base Polymorphism (SNP) loss of heterozygosity (LOH), (x) Kras mutation, (xi) methylation of promoter region of tumor-related genes Different, and (xii) based on NSCLC having one or more features selected from the group consisting of the difference in albumin uptake, methods are also provided.

  As used herein, NSCLC indicates (a) squamous cell carcinoma, (b) differential levels of caveolin-1 (CAV1), (c) differential levels of SPARC, (d) levels of hypoxia markers. Difference, (e) difference in level of tumor acidity, (f) difference in level of gp60, (g) difference in level of thymidylate synthase (TS), (h) level of S-phase kinase-related protein (Skp2) Difference, (i) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (j) difference of Kras mutation, (k) difference in methylation of promoter region of tumor-associated gene, and (l A) a method of treating NSCLC in an individual where it has been found to have one or more characteristics selected from the group consisting of differences in albumin uptake, wherein the treatment comprises i) An effective amount of a composition comprising nanoparticles comprising Ritakiseru and albumin, comprising the step of administering a platinum-based agent ii) an effective amount, a method is further provided.

  Also herein, (a) selecting individuals with NSCLC, wherein NSCLC is (i) squamous cell carcinoma, (ii) caveolin-1 (CAV1) level difference, (iii) Differences in levels of SPARC, (iv) differences in levels of hypoxia markers, (v) differences in levels of tumor acidity, (vi) differences in levels of gp60, (vii) levels of thymidylate synthase (TS) Differences, (viii) differences in levels of S phase kinase-related protein (Skp2), (ix) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (x) differences in Kras mutation, (xi) (A) having one or more characteristics selected from the group consisting of :) a difference in methylation of the promoter region of a tumor-related gene, and (xii) a difference in albumin uptake. And (b) administering an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin to the individual thus selected, and ii) an effective amount of a platinum-based agent. A method of treating NSCLC is also provided.

  In the present specification, a method for evaluating whether or not a treatment is effective for an individual having NSCLC, comprising: (a) a squamous cell carcinoma; (b) a difference in the level of caveolin-1 (CAV1); ) SPARC level difference, (d) hypoxia marker level difference, (e) tumor acidity level difference, (f) gp60 level difference, (g) thymidylate synthase (TS) level (H) differences in levels of S phase kinase-related protein (Skp2), (i) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (j) differences in Kras mutation, ( k) assessing one or more characteristics of NSCLC selected from the group consisting of a difference in promoter region methylation in a tumor-associated gene, and (l) a difference in albumin uptake, comprising NSCL One or more of the characteristics of the individual indicates that the treatment is responsive to the individual, the treatment comprising i) an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin; and ii) an effective amount of a platinum-based A method comprising an agent is also provided.

  In addition, herein, a method for identifying an individual with NSCLC that is likely to respond to treatment comprising a) a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent. (A) (i) Squamous cell carcinoma, (ii) Caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) Hypoxia marker level difference, (V) a difference in the level of tumor acidity, (vi) a difference in the level of gp60, (vii) a difference in the level of thymidylate synthase (TS), (viii) a difference in the level of S-phase kinase-related protein (Skp2), (Ix) Loss of heterozygosity (LOH) of single nucleotide polymorphism (SNP), (x) Difference of Kras mutation, (xi) Methylation of promoter region of tumor-related gene Assessing one or more characteristics of NSCLC selected from the group consisting of a difference in crystallization, and (xii) a difference in albumin uptake; (B) (i) squamous cell carcinoma; (ii) caveolin -1 (CAV1) level difference, (iii) SPARC level difference, (iv) hypoxia marker level difference, (v) tumor acidity level difference, (vi) gp60 level difference , (Vii) differential levels of thymidylate synthase (TS), (viii) differential levels of S phase kinase-related protein (Skp2), (ix) loss of single nucleotide polymorphism (SNP) heterozygosity (LOH) , (X) Kras mutation difference, (xi) tumor-related gene promoter region methylation difference, and (xii) albumin uptake difference More selected, and a step of identifying individuals who have one or more features of NSCLC, a method is provided.

  Also herein, a combination therapy comprising a) a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based drug is marketed for use in a subpopulation of NSCLC individuals. A method comprising: (i) squamous cell carcinoma; (ii) caveolin-1 (CAV1) level difference; (iii) SPARC level difference; (iv) hypoxia marker level difference; v) differences in tumor acidity levels, (vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) differences in levels of S-phase kinase-related protein (Skp2), ix) Loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (x) Kras mutation, (xi) Tumor-related inheritance To treat a subpopulation of individuals characterized by a subpopulation of individuals having one or more NSCLC characteristics selected from the group consisting of: a difference in promoter region methylation, and (xii) a difference in albumin uptake Also provided is a method comprising informing a target audience about the use of a combination therapy.

  In some embodiments for any of the methods, the difference in the level of tumor acidity is the difference in the level of carbonic anhydrase 9 (CA-9) and / or the level of LDH (eg, LDH-5). This is evident by the difference. In some embodiments for any of the methods, the difference in the level of a hypoxia marker is a difference in the level of HIF-1α, a difference in the level of HIF-2α, and / or a differentiated embryo chondrocyte expression gene 1 (differentiated embryo-chronocycle expressed gene 1 (DEC-1)).

  In some embodiments for any of the above methods, the method comprises a measurable reduction in tumor size, a measurable reduction in evidence of disease or disease progression, complete response, partial response, disease stability, no progression It results in increased survival or prolonged progression-free survival, increased overall survival or prolonged overall survival, or reduced toxicity.

  In some embodiments for any of the above methods, the level difference is the expression level of normal or control cells, a given patient population, or overexpression (high expression) compared to an internal control. Or underexpression (low expression). In some embodiments, the level is between an individual and a normal patient population, between an individual and an NSCLC patient population with different NSCLC histological characteristics, or between an individual and an NSCLC histological characteristic of the same NSCLC patient population. Compare with.

  In some embodiments, the level difference is determined in tumor tissue, normal tissue adjacent to the tumor, normal tissue distal to the tumor, or peripheral blood lymphocytes.

  In some embodiments for any of the methods described herein, the NSCLC is squamous cell carcinoma (ie epidermoid carcinoma), large cell carcinoma, adenocarcinoma, adenosquamous Epithelial cancer, polymorphic element, sarcoma-like element, or cancer with sarcoma element, carcinoid tumor, or salivary gland cancer. In some embodiments, the NSCLC is a squamous cell cancer. In some embodiments for any of the methods described herein, the NSCLC is a latent tumor, stage 0 tumor, stage I tumor, stage II tumor, stage IIIA. Tumor, stage IIIB tumor, or stage IV tumor. In some embodiments for any of the methods described herein, the NSCLC is early NSCLC, non-metastatic NSCLC, primary NSCLC, advanced NSCLC, locally advanced NSCLC, metastatic NSCLC, remission phase NSCLC or recurrent NSCLC. In some embodiments, the NSCLC is resectable local NSCLC, unresectable local NSCLC, or unresectable NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC, PS 0-1, and FEV 1> 800 ml. In some embodiments for any of the methods described herein, the method is a method of treating NSCLC as a first line therapy or a second line therapy.

In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (eg, 50 mg / m 2 , 75 mg / m 2 , or 100 mg / m 2 ). And an effective amount of a platinum-based drug is about AUC = 2 to about AUC = 6 (eg, AUC = 3, AUC = 4.5, or AUC = 6). In some embodiments, an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week, and an effective amount of a platinum-based agent is administered every 3 weeks. In some embodiments, the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (administered once a week) and the effective amount of the platinum-based agent is about AUC = 2 to about AUC = 6 (once administered every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 100 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 6 ( Once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 75 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 4. 5 (once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 3 ( Once every 3 weeks). In some embodiments, the paclitaxel nanoparticle composition and / or the platinum-based agent is administered intravenously. In some embodiments, the paclitaxel nanoparticle composition and the platinum-based agent are administered intravenously.

  In some embodiments, the albumin is human serum albumin. In some embodiments, the nanoparticle comprises paclitaxel coated with albumin. In some embodiments, the average particle size of the nanoparticles in the nanoparticle composition is about 200 nm or less (such as less than about 200 nm). In some embodiments, the composition comprises an albumin stabilized nanoparticulate formulation of paclitaxel (Nab-paclitaxel (Abraxane®)). In some embodiments, the composition is Nab-paclitaxel (Abraxane®).

  In some embodiments, the platinum-based agent covalently binds to DNA, crosslinks, inhibits DNA synthesis, and / or inhibits transcripts. In some embodiments, the platinum-based agent is carboplatin, cisplatin, or oxaliplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin.

  In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered sequentially, co-administered, or co-administered.

  Also provided are compositions (such as pharmaceutical compositions), medicaments, kits, and unit doses useful for the methods described herein.

These and other aspects and advantages of the present invention will become apparent from the subsequent detailed description and the appended claims. It is understood that one, some or all of the characteristics of the various embodiments described herein can be combined to form other embodiments of the invention.
In certain embodiments, for example, the following are provided:
(Item 1)
A method of treating NSCLC in an individual comprising:
a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin;
b) with an effective amount of a platinum-based drug
Treatment comprising: (i) squamous cell carcinoma, (ii) differential level of caveolin-1 (CAV1), (iii) differential level of SPARC, (iv) hypoxia marker Level difference, (v) level of tumor acidity, (vi) level difference of gp60, (vii) level difference of thymidylate synthase (TS), (viii) of S phase kinase related protein (Skp2) Level differences, (ix) loss of heterozygosity for single nucleotide polymorphisms (SNPs) (LOH), (x) differences in Kras mutations, (xi) differences in the methylation of promoter regions of tumor-related genes, and (Xii) A method based on NSCLC having one or more characteristics selected from the group consisting of differences in albumin uptake.
(Item 2)
(Ii) Squamous cell carcinoma, (ii) Caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) Hypoxia marker level difference, (v) Tumor acidity (Vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) differences in levels of S-phase kinase-related protein (Skp2), (ix) single nucleotides Group consisting of difference in loss of heterozygosity (LOH) of type (SNP), (x) difference in Kras mutation, (xi) difference in promoter region methylation of tumor-associated gene, and (xii) difference in albumin uptake 2. The method of item 1, comprising selecting an individual for treatment based on the more selected feature.
(Item 3)
2. The method of item 1, wherein the treatment is based on NSCLC, which is a squamous cell cancer.
(Item 4)
2. The method of item 1, wherein the treatment is based on NSCLC with differences in the level of hypoxia.
(Item 5)
5. The method of item 4, wherein the difference in the level of hypoxia is a difference in the level of carbonic anhydrase-9 (CA-9) or a level of LDH (eg, LDH-5).
(Item 6)
The method of item 1, wherein the treatment is based on a difference in the level of tumor acidity.
(Item 7)
Item 7. The difference in the level of tumor acidity is based on a difference in the level of HIF-1α, a difference in the level of HIF-2α, or a difference in the level of differentiated embryo chondrocyte expression gene 1 (DEC-1). the method of.
(Item 8)
The method of item 1, wherein the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is about 50 mg / m 2 to about 125 mg / m 2 .
(Item 9)
The method of item 1, wherein the composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week.
(Item 10)
2. The method of item 1, wherein the effective amount of the platinum-based agent is about AUC = 2 to about AUC = 6.
(Item 11)
The method of item 1, wherein the platinum-based drug is administered once every three weeks.
(Item 12)
The effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is 100 mg / m 2 once a week, and the effective amount of the platinum-based drug is administered once every 3 weeks. A method according to item 1, wherein AUC = 6.
(Item 13)
Item 2. The method according to Item 1, wherein the paclitaxel in the nanoparticles is coated with albumin.
(Item 14)
The method of item 1, wherein the average diameter of the nanoparticles in the composition is about 200 nm or less.
(Item 15)
2. The method of item 1, wherein the NSCLC is stage IIIB NSCLC or stage IV NSCLC.
(Item 16)
2. The method of item 1, wherein the composition comprising nanoparticles comprising paclitaxel and albumin, and the platinum-based agent are administered parenterally.
(Item 17)
18. The method of item 16, wherein the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously.
(Item 18)
The method of item 1, wherein the platinum-based agent is carboplatin.
(Item 19)
Item 2. The method according to Item 1, wherein the individual is a human.
(Item 20)
The method of item 1, further comprising administration of chest radiation.
(Item 21)
Wherein the effective amount of the composition comprising nanoparticles comprising paclitaxel and an albumin is from about 20 mg / m 2 ~ about 60 mg / m 2 administered once a week, wherein the effective amount of a platinum-based drug, a week Item 20 wherein the single dose of about AUC = 2 to about AUC = 6 and the synchronic chest radiation is about 25 to about 40 fractions via 3D conformal or intensity modulation methods The method described in 1.
(Item 22)
A method for assessing whether treatment is effective for an individual with NSCLC, comprising: (a) squamous cell carcinoma; (b) a difference in caveolin-1 (CAV1) levels; (c) a level of SPARC Difference, (d) hypoxia marker level difference, (e) tumor acidity level difference, (f) gp60 level difference, (g) thymidylate synthase (TS) level difference, (h ) Differences in the level of S-phase kinase-related protein (Skp2), (i) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (j) difference in Kras mutation, (k) tumor-related gene Assessing one or more characteristics of NSCLC selected from the group consisting of a difference in methylation in the promoter region of and a difference in (l) albumin uptake, wherein One or more of the symptoms may indicate that the treatment will respond to the individual, the treatment,
i) an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin;
ii) an effective amount of a platinum-based drug;
Including a method.
(Item 23)
a) a composition comprising nanoparticles comprising paclitaxel and albumin;
b) with platinum-based drugs
A method of identifying individuals with NSCLC that are likely to respond to treatment comprising:
(A) (i) Squamous cell carcinoma, (ii) Caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) Hypoxia marker level difference, (v) (Vi) differences in levels of tumor acidity, (vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) differences in levels of S-phase kinase-related protein (Skp2), (ix) Single nucleotide polymorphism (SNP) loss of heterozygosity (LOH) difference, (x) Kras mutation difference, (xi) Difference in promoter region methylation of tumor associated genes, and (xii) Difference in albumin uptake Evaluating one or more features of NSCLC selected from the group consisting of:
(B) (i) squamous cell carcinoma, (ii) differential level of caveolin-1 (CAV1), (iii) differential level of SPARC, (iv) differential level of hypoxia marker, (v) (Vi) differences in levels of tumor acidity, (vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) differences in levels of S-phase kinase-related protein (Skp2), (ix) Single nucleotide polymorphism (SNP) loss of heterozygosity (LOH) difference, (x) Kras mutation difference, (xi) Difference in promoter region methylation of tumor associated genes, and (xii) Difference in albumin uptake Identifying an individual having one or more characteristics of NSCLC selected from the group consisting of:
Including a method.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of combination therapy for treating NSCLC by administering a) a composition comprising nanoparticles comprising paclitaxel and albumin, and b) a platinum-based agent (such as carboplatin). provide. In another aspect, a method of treating NSCLC in an individual in need thereof, comprising: (a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and (b) an effective amount of a platinum base. A method comprising the steps of:

  Also provided are compositions (such as pharmaceutical compositions), medicaments, kits, and unit doses useful for the methods described herein.

Definitions As used herein, “treatment” or “treating” is an approach for obtaining a benefit or desired result, including clinical results. For purposes of the present invention, beneficial or desired clinical results include the following: alleviating one or more symptoms resulting from the disease, reducing the extent of the disease, stabilizing the disease (eg, disease Preventing or delaying the progression of the disease), preventing or delaying the spread of the disease (eg metastasis), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease , Improving disease status, providing disease remission (partial response or complete response), reducing the dose of one or more other medications needed to treat the disease, Includes, but is not limited to, one or more of delaying disease progression, improving quality of life, and / or prolonging survival. “Treatment” also includes a reduction in the pathological consequences of NSCLC. The methods of the present invention contemplate any one or more of these aspects of treatment.

  The term “individual” refers to mammals, including but not limited to humans, cows, horses, cats, dogs, rodents, or primates. The individual is preferably a human.

  As used herein, an “at risk” individual is an individual who is at risk of developing NSCLC. An “at risk” individual may or may not have a detectable disease, and may exhibit a detectable disease prior to the treatment methods described herein. , Not shown. “At risk” means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of NSCLC as described herein. Individuals with one or more of these risk factors are more likely to develop cancer than individuals without these risk factor (s).

  “Adjuvant setting” refers to a clinical situation in which an individual has a history of NSCLC and treatment has generally responded (but is not necessarily required) to this individual. Treatment includes, but is not limited to, surgery (eg, surgical resection), radiation therapy, and chemotherapy. However, because of their history of NSCLC, these individuals are considered at risk of developing the disease. Treatment or administration in the “adjuvant situation” refers to a subsequent mode of treatment. The degree of risk (eg, when an individual in an adjuvant situation is considered “high risk” or “low risk”) depends on several factors and may depend on the degree of disease in the initial treatment. Most usual.

  “Neoadjuvant setting” refers to a clinical situation where the method is performed prior to the main / critical treatment.

  As used herein, “delaying” the onset of NSCLC refers to postponing, inhibiting, slowing, delaying, delaying, stabilizing and / or delaying the onset of NSCLC. Means. This delay can be various lengths of time depending on the history of the disease and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can encompass prevention in that the individual does not effectively develop the disease. A method of “delaying” the onset of NSCLC reduces the likelihood of disease onset in a given time frame and / or the extent of disease in a given time frame compared to not using this method It is a method to reduce. Such comparisons are typically based on clinical studies using a statistically significant number of subjects. The onset of NSCLC includes standard methods including but not limited to computed tomography (CAT scan), magnetic resonance imaging (MRI), abdominal ultrasound, blood clot, arteriography, or biopsy Can be detected. Onset may also refer to progression of NSCLC that may not be detected in the early stages, including occurrence, recurrence, and onset.

  As used herein, “combination therapy” means that a first agent is administered with another agent. “With” refers to administration of one treatment modality in addition to another treatment modality, such as administration of a nanoparticle composition described herein in addition to administration of other agents to the same individual. Point to. “With” by itself refers to administration of one treatment modality before, during or after delivery of other treatment modalities to an individual. Such combinations are considered a single treatment regime or part of a treatment regime.

  As used herein, the term “effective amount” refers to a specified disorder, condition, such as ameliorating, alleviating, reducing and / or delaying one or more of its symptoms. Or refers to an amount of a compound or composition sufficient to treat a disease. For NSCLC, an effective amount reduces the tumor and / or reduces the growth rate of the tumor (such as suppressing tumor growth) or prevents or delays other harmful cell growth in NSCLC. Including a sufficient amount. In some embodiments, the effective amount is an amount sufficient to delay the onset of NSCLC. In some embodiments, the effective amount is an amount sufficient to prevent or delay recurrence. An effective amount can be administered in one or more administrations. In the case of NSCLC, an effective amount of the drug or composition can (i) reduce the number of NSCLC cells, (ii) reduce the size of the tumor, and (iii) enter the peripheral organ Can inhibit, delay, slow down, and preferably stop NSCLC cancer cell invasion to some extent, and (iv) inhibit tumor metastasis (ie slow down, preferably stop) to some extent (Vi) can inhibit tumor growth, (vi) can prevent or delay tumor development and / or recurrence, and / or (vii) NSCLC One or more of the symptoms associated with can be alleviated to some extent.

  As used herein, the term “simultaneous administration” refers to a first therapy and a second therapy in combination therapy within about 15 minutes, such as within about 10, 5, or 1 minute. Means administered at time intervals. When the first therapy and the second therapy are administered simultaneously, the first therapy and the second therapy are in the same composition (eg, a composition comprising both the first therapy and the second therapy). It can also be included, or it can be included in a separate composition (eg, the first therapy is included in one composition and the second therapy is included in another composition).

  As used herein, the term “sequential administration” refers to a first therapy and a second therapy in combination therapy of about 15 such as any of about 20, 30, 40, 50, 60 minutes or more. It is meant to be administered at time intervals greater than minutes. The first therapy can be administered first and the second therapy can be administered first. The first therapy and the second therapy can be contained in separate compositions, which can be contained in the same package or kit, or in different packages or kits.

  As used herein, the term “concurrent administration” means that the administration of the first therapy and the administration of the second therapy in the combination therapy overlap each other.

  As used herein, “pharmaceutically acceptable” or “pharmacologically compatible” means a material that is not biologically or otherwise harmful, eg, a material is any Into a pharmaceutical composition that is administered to a patient without causing a significantly detrimental biological effect or interacting in a deleterious manner with any of the other components of the composition in which it is contained. And can be incorporated. A pharmaceutically acceptable carrier or excipient is preferably incorporated based on the “Guidelines for Inactive Ingredients” that meet toxicity test and manufacturing test requirements and / or prepared by the US Food and Drug Administration It is done.

  As used herein, “adverse event” or “AE” refers to any inconvenience in a patient receiving a commercially available drug or participating in a clinical trial and receiving a test or non-test drug. Refers to the occurrence of a serious medical event. AE is not necessarily causal with patient treatment. Thus, an AE, whether considered to be associated with a pharmaceutical, or not, is any undesirable sign, symptom, or disease that is temporarily associated with the use of the pharmaceutical, and an unintended sign, symptom, or It can be a disease. Many AEs can be associated with the progression of the patient's underlying malignancy. AE includes progression of an existing disease, increased frequency or increased intensity of an existing episodic event or episode state, a condition detected or diagnosed after administration of a test drug (which may have existed before the start of the study Including, but not limited to, persistent and long-term diseases or symptoms that exist at baseline and have progressed after the start of the study. AEs are generally present at the start of a study in a medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, or blood transfusion) (but the condition that results in the medical or surgical procedure is an adverse event) Hospitalization or procedures made for non-urgent purposes that are not associated with the occurrence of an abnormal disease, condition or test value, occurrence of an adverse medical event (eg, cosmetic) Hospitalization for surgery or non-emergency surgery, or social / convenience hospitalization), the disease under study, or signs / symptoms associated with this disease, if not as severe as expected for the patient's condition, and Does not include overdose of study drug without any clinical signs or symptoms.

  As used herein, “serious adverse events” (SAEs) are: a) the occurrence of a fatal adverse medical event, b) life-threatening (the immediate occurrence of that event when it occurs) Occurrence of adverse medical events (defined as risk of death), c) occurrence of adverse medical events resulting in long-term or serious disability or incapacity, d) hospitalization required or existing Occurrence of adverse medical events that prolong hospitalization (exception: hospitalizations for non-urgent treatment of existing conditions that did not progress during the study period are not considered adverse events. Complications occurring during hospitalization are If it is AE and complications prolong hospitalization, the event is a serious event), e) of an adverse medical event that is a congenital anomaly / birth deficit in the offspring of a dosed patient Occurrence, or f) patient The above definitions that may put the patient at risk if the association with the underlying disorder is not clear and may require intervention to prevent one of the outcomes listed above Refers to the occurrence of any adverse medical event at any dose, including, but not limited to, the occurrence of adverse medical events that are not covered by. “Lack of efficacy” (progressive disease) is not considered AE. If signs and symptoms or clinical sequelae resulting from lack of efficacy meet the definition of AE or SAE, they should be reported.

  To assess response based on the target lesion, the following definitions can be used: “complete response” or “CR” refers to the disappearance of all target lesions and is referred to as “partial response” or “PR”. Refers to a decrease in SLD of the target lesion by at least 30% relative to baseline sum of major diameters (SLD), where “disease stable” or “SD” is the lowest (nadir) at which treatment is initiated. ) With respect to SLD, this refers to a reduction in target lesion that is not sufficient to evaluate as PR, or an increase in target lesion that is not sufficient to evaluate as PD, where “disease progression” or “PD” Refers to an increase in the SLD of the target lesion by at least 20% or the presence of one or more new lesions relative to the lowest SLD recorded when initiated, “unassessable” or “U "Refers to a target lesion that was present at baseline but was not measured or could not be evaluated, so it was not possible to determine the status of that particular tumor for the time point in question (at some point the SLD If it cannot be determined and the PD rules do not apply, then a response of CR, PR, or SD cannot be assigned at that time, and the response at that point will be UE), “Not applicable” or “ “NA” means no target lesion was identified at baseline (patients with no identified target lesion at baseline cannot be assessed for response. These patients are assessed only for progression. ), “Not performed” or “ND” refers to the absence of a scan to evaluate the target lesion at this point.

  To assess non-target lesions, the following definitions for response assessment can be used: “complete response” or “CR” refers to the disappearance of all non-target lesions and refers to “disease stability” or “ “SD” refers to one or more long-term non-target lesions that are not assessed as CR or PD, and “disease progression” or “PD” refers to “clear progression” of existing non-target lesion (s). , Or the appearance of one or more new lesion (s) is considered disease progression (the subject's PD is assessed for a point in time based solely on the progression of the non-target lesion (s)) In some cases, it is necessary to meet further criteria, in which case the lesion (s) for which PD is assessed must be assessed retroactively from the baseline (or lowest) and compared to the time of the problem. In this case PD for non-target lesion (s) is measured by an increase in SLD of these lesion (s) by 20% or more at the time of progression and the longest diameter (LD) of the lesion (s) is 10 mm or more. If non-target lesion (s) do not meet the described quantitative criteria, these non-target lesions are not evaluated as advanced.Pleural effusion, ascites, endocardium For fluid leaching and other bodily fluid collections, subjects who are estimated to exceed 500 cc in this bodily fluid and cannot be attributed to benign causes identified by radiography, are otherwise stable or responsive "Unassessable" or "UE" means identifying the time point in question because it was present in the baseline but was not measured or assessed Refers to any non-target lesion for which determination of tumor status is not possible, “N / A” or “NA” refers to no non-target lesion identified at baseline, “None” or “ND” "" Means that at this point no scan was made to evaluate non-target lesions.

  As used herein, “at the beginning of treatment” or “baseline” refers to an initial exposure to a treatment comprising a) a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent. Refers to the time point or time point before the first exposure. In some embodiments, “at the beginning of treatment” or “baseline” is about 6 months prior to treatment comprising a) a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent. Either 3 months ago, 2 months ago, 1 month ago, or several days ago. In some embodiments, “at the beginning of treatment” is immediately prior to the first exposure to treatment comprising a) a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent, Or consistent with initial exposure.

  As used herein, “based on” assesses, determines, or measures the patient characteristics described herein (and preferably selects a suitable patient to receive treatment). Is included.

  As used herein, “highly likely to respond” or “response” means measurable reduction in tumor size, measurable reduction in evidence of disease or disease progression, complete response, partial response, disease stability Any improvement, whether clinical or non-clinical, selected from, but not limited to, increased progression-free survival or prolonged progression-free survival, or increased overall survival or prolonged overall survival Or refers to a positive response.

  “Progression free survival” (PFS) refers to the length of time during and after treatment when the cancer does not grow. Progression-free survival encompasses the length of time the patient experienced a complete or partial response as well as the length of time that the patient experienced disease stabilization.

  “Complete response” (CR) of treatment defines a patient whose disease is evaluable but not measurable and all evidence of the tumor and disease has disappeared.

  A “partial response” (PR) of treatment defines that a patient with something less than a complete response was simply categorized as having a partial response.

  “Disease stable” (SD) indicates that the patient is stable.

  When the quality of life related to the patient's health is “used as a base” to administer the treatment methods described herein or to select the treatment methods described herein, the therapist The quality of life or limitations associated with the patient's health are assessed before and / or during treatment and the conclusions obtained are: (a) the expectation that the individual will receive initial treatment (s) Or estimated fit, (b) the expected or estimated incompatibility of an individual receiving initial treatment (s), (c) the response of treatment, (d) the individual receiving continuous treatment (s) Of predicted or estimated fit, (e) expected or estimated incompatibility of an individual receiving continuous treatment (s), (f) dose adjustment, or (g) prediction of potential clinical benefit Evaluate one of It used to Rutoki. As well understood by those skilled in the art, an assessment of the quality of life related to patient health in a clinical setting can be used to initiate, continue, adjust, and / or adjust the parameters described herein. Clearly show that it was used as a base for interruption.

  As used herein, “cell”, “host cell”, or “recombinant host cell” are terms used interchangeably. It is to be understood that such terms refer not only to the particular subject cell, but also to the progeny or potential progeny cells of such a cell. Such progeny cells may not actually be identical to the parental cell, as certain modifications may occur in subsequent generations due to mutations or environmental effects, but again here Included within the scope of the terms used.

  It is understood that aspects and embodiments of the invention described herein encompass aspects and embodiments “consisting of” and / or aspects and embodiments “consisting essentially of”. I want.

  Reference herein to “approximately” values or parameters encompasses (and describes) variations to that value or parameter itself. For example, description referring to “about X” includes description of “X”.

  As used herein and in the appended claims, the singular forms “a”, “or”, and “the” do not clearly indicate different contexts. As long as it includes a plurality of instructions.

  As will be apparent to those skilled in the art, an individual that is evaluated for treatment, selected for treatment, and / or treated is an individual in need of such activity.

Methods of treating NSCLC The present invention is a method of treating NSCLC in an individual (eg, a human) comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of A method is provided comprising the step of administering a platinum-based agent.

  The methods herein are applicable to multiple histological types of NSCLC. NSCLC is a squamous cell carcinoma (ie epidermoid carcinoma), large cell carcinoma, adenocarcinoma, adenosquamous carcinoma, polymorphic element, sarcoma-like element, or cancer with sarcoma element, carcinoid It can be a tumor or a salivary gland cancer. In some embodiments, the NSCLC is a squamous cell cancer. In some embodiments, the squamous cell carcinoma is papillary squamous cell carcinoma, clear cell squamous cell carcinoma, small cell squamous cell carcinoma, or basal squamous cell carcinoma. In some embodiments, the NSCLC is a glandular cancer. In some embodiments, the adenocarcinoma is acinar cancer, papillary cancer, bronchoalveolar cancer (eg, non-mucous cell type, mucous cell type, mucous cell type and non-mucous cell type) Mixed or undefined cell type), solid adenocarcinoma with mucus, adenocarcinoma with mixed subtype, fully differentiated fetal adenocarcinoma, mucinous (colloidal) adenocarcinoma, mucinous Cystic adenocarcinoma, signet ring adenocarcinoma, or clear cell gland cancer. In some embodiments, the large cell cancer is a large cell neuroendocrine cancer, mixed large cell neuroendocrine cancer, basal cell carcinoma, lymphoepithelioma-like cancer, clear cell carcinoma, or rhabdoid Large cell cancer with phenotype. In some embodiments, the cancer with a polymorphic element, sarcoma-like element, or sarcoma element is cancer with spindle cells and / or giant cells, spindle cell cancer, giant cell cancer, carcinosarcoma Or lung blastoma. In some embodiments, the type of salivary adenocarcinoma is mucinous epidermoid cancer or adenoid cyst cancer.

  NSCLC of any of the methods herein is a latent tumor, a stage 0 tumor, a stage I tumor (stage IA (T1, N0, M0) tumor, or stage IB (T2, N0) , M0) tumors), stage II tumors (stage IIA (T1, N1, M0) tumors, and stage IIB (T2, N1, M0) tumors), stage IIIA tumors (T1, N2) , M0, T2, N2, M0, T3, N1, M0, or T3, N2, M0), stage IIIB tumor (any T, N3, M0, or T4, any N, M0), or stage It can be an IV tumor (any T, any N, M1). In some embodiments for any of the methods described herein, the NSCLC is early NSCLC, non-metastatic NSCLC, primary NSCLC, advanced NSCLC, locally advanced NSCLC, metastatic NSCLC, remission phase NSCLC or recurrent NSCLC. In some embodiments, the NSCLC is resectable local NSCLC, unresectable local NSCLC, or unresectable NSCLC. In some embodiments, the NSCLC is an unresectable stage IV NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC, PS 0-1, and FEV 1> 800 ml.

  The methods provided herein can be practiced in an adjuvant setting. In some embodiments, the method is performed in a neoadjuvant situation. That is, the method can be performed before primary / root treatment. In some embodiments, this treatment is used to treat a previously treated individual. Any of the treatment methods provided herein can be used to treat an individual who has not been previously treated. In some embodiments, the method is used as a first line therapy. In some embodiments, the method is used as a second line therapy.

  In some embodiments for any of the methods described herein, the composition comprises nanoparticles comprising paclitaxel and albumin (such as human serum albumin), wherein the paclitaxel in the nanoparticles is albumin. It is coated with. In some embodiments, the average particle size of the nanoparticles in the composition is about 200 nm or less (such as less than about 200 nm). In some embodiments, the composition comprises Nab-paclitaxel (Abraxane®). In some embodiments, the composition is Nab-paclitaxel (Abraxane®). In some embodiments, the nanoparticle composition and the platinum-based agent have a synergistic effect on the treatment of NSCLC.

  Platinum-based agents covalently bind to DNA, crosslink strands, inhibit DNA synthesis, and / or inhibit transcripts. In some embodiments, the platinum-based agent is carboplatin, cisplatin, or oxaliplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin.

In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (eg, 50 mg / m 2 , 75 mg / m 2 , or 100 mg / m 2 ). And an effective amount of a platinum-based drug is about AUC = 2 to about AUC = 6 (eg, AUC = 3, AUC = 4.5, or AUC = 6). In some embodiments, an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week, and an effective amount of a platinum-based agent is administered every 3 weeks. In some embodiments, the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (administered once a week) and the effective amount of the platinum-based agent is about AUC = 2 to about AUC = 6 (once administered every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 100 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 6 ( Once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 75 mg / m (administered once a week) and an effective amount of a platinum-based drug is about AUC = 4.5 (Administered once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 3 ( Once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 40 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 2 ( Once a week). In some embodiments, the paclitaxel nanoparticle composition and / or the platinum-based agent is administered intravenously. In some embodiments, the paclitaxel nanoparticle composition and the platinum-based agent are administered intravenously.

  In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered sequentially, co-administered, or co-administered.

  In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin is administered without any pre-medication of steroids and / or without prophylaxis with G-CSF.

For example, a method of treating NSCLC in an individual in need thereof, comprising: (a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and (b) an effective amount of a platinum-based agent. An effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 100 mg / m 2 (once weekly) and an effective amount of a platinum-based drug is AUC = 6, A method is provided. In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin and a platinum-based agent are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the NSCLC is a squamous cell cancer.

In some embodiments, a method of treating NSCLC in an individual in need thereof, wherein the individual (a) comprises an effective amount of a composition comprising nanoparticles comprising paclitaxel coated with albumin; and (b) Administering an effective amount of a platinum-based drug, wherein the effective amount of the composition comprising nanoparticles comprising paclitaxel coated with albumin is 100 mg / m 2 (once weekly) A method is provided wherein the effective amount of drug is AUC = 6. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin and a platinum-based agent are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the NSCLC is a squamous cell cancer.

In some embodiments, a method of treating NSCLC in an individual in need thereof, comprising: (a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin comprising: Administering an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin, comprising administering a composition having an average size of nanoparticles of about 200 nm or less and (b) an effective amount of a platinum-based agent. A method is provided wherein the dose is 100 mg / m 2 (once weekly) and the effective amount of platinum-based drug is AUC = 6. In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the NSCLC is a squamous cell cancer.

In some embodiments, a method of treating NSCLC in an individual in need thereof, wherein the individual comprises (a) an effective amount of a composition comprising nanoparticles comprising paclitaxel coated with albumin comprising: Administering a composition wherein the average size of the nanoparticles in the particle composition is about 200 nm or less, and (b) an effective amount of a platinum-based agent, comprising nanoparticles comprising paclitaxel coated with albumin A method is provided wherein the effective amount of the composition is 100 mg / m 2 (administered once a week) and the effective amount of the platinum-based drug is AUC = 6. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin, as well as a platinum-based agent is administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the NSCLC is a squamous cell cancer.

In some embodiments, a method of treating NSCLC in an individual in need thereof comprising: (a) an effective amount of Nab-paclitaxel (Abraxane®); and (b) an effective amount of platinum. An effective amount of Nab-paclitaxel (Abraxane®) is 100 mg / m 2 (once weekly) and an effective amount of platinum-based drug is AUC = 6 A method is provided. In some embodiments, Nab-paclitaxel (Abraxane®) is administered once a week and the platinum-based agent is administered once every three weeks. In some embodiments, Nab-paclitaxel (Abraxane®) and a platinum-based drug are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the NSCLC is a squamous cell cancer.

In some embodiments, a method of treating NSCLC in an individual in need thereof comprising: (a) an effective amount of Nab-paclitaxel (Abraxane®); and (b) an effective amount of carboplatin. A method is provided wherein the effective amount of Nab-paclitaxel (Abraxane®) is 100 mg / m 2 (once weekly) and the effective amount of carboplatin is AUC = 6 Is done. In some embodiments, Nab-paclitaxel (Abraxane®) is administered once a week and carboplatin is administered once every three weeks. In some embodiments, Nab-paclitaxel (Abraxane®) and carboplatin are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the NSCLC is a squamous cell cancer.

A method of treating NSCLC in an individual in need thereof comprising administering to an individual an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin, and b) an effective amount of a platinum-based agent. There is also provided a method wherein NSCLC is a squamous cell cancer. In some embodiments, the effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 100 mg / m 2 (administered once a week) and the effective amount of a platinum-based drug is AUC = 6. In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin.

In some embodiments, a method of treating NSCLC in an individual in need thereof comprising: a) an effective amount of a composition comprising a) nanoparticles comprising paclitaxel coated with albumin; and b) an effective amount. A method wherein the NSCLC is a squamous cell cancer. In some embodiments, the effective amount of a composition comprising nanoparticles comprising paclitaxel coated with albumin is 100 mg / m 2 (once weekly) and the effective amount of a platinum-based drug is AUC = 6 It is. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin, as well as a platinum-based agent is administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin.

In some embodiments, a method of treating NSCLC in an individual in need thereof comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin comprising: A method is provided wherein the method comprises administering a composition having an average nanoparticle size of about 200 nm or less and b) an effective amount of a platinum-based agent, wherein the NSCLC is a squamous cell cancer. In some embodiments, the effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 100 mg / m 2 (administered once a week) and the effective amount of a platinum-based drug is AUC = 6. In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin and a platinum-based agent are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin.

In some embodiments, a method of treating NSCLC in an individual in need thereof comprising: a) an effective amount of a composition comprising a) a nanoparticle comprising paclitaxel coated with albumin comprising: There is provided a method comprising administering a composition wherein the average size of nanoparticles in the composition is about 200 nm or less, and b) an effective amount of a platinum-based agent, wherein the NSCLC is a squamous cell cancer. The In some embodiments, the effective amount of a composition comprising nanoparticles comprising paclitaxel coated with albumin is 100 mg / m 2 (once weekly) and the effective amount of a platinum-based drug is AUC = 6 It is. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, a composition comprising nanoparticles comprising paclitaxel coated with albumin and a platinum-based agent are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy. In some embodiments, the platinum-based agent is carboplatin.

In some embodiments, a method of treating NSCLC in an individual in need thereof comprising: a) an effective amount of Nab-paclitaxel (Abraxane®); and b) an effective amount of a platinum-based A method is provided comprising administering an agent, wherein the NSCLC is a squamous cell cancer. In some embodiments, the effective amount of Nab-paclitaxel (Abraxane®) is 100 mg / m 2 (administered once a week) and the effective amount of platinum-based drug is AUC = 6. In some embodiments, Nab-paclitaxel (Abraxane®) is administered once a week and the platinum-based agent is administered once every three weeks. In some embodiments, Nab-paclitaxel (Abraxane®) and a platinum-based drug are administered intravenously. In some embodiments, the NSCLC is a progressive NSCLC. In some embodiments, the method is used as a first line therapy.

In some embodiments, a method of treating NSCLC in an individual in need thereof, wherein the individual is administered a) an effective amount of Nab-paclitaxel (Abraxane®) and b) an effective amount of carboplatin. A method is provided wherein the NSCLC is a squamous cell cancer. In some embodiments, the effective amount of Nab-paclitaxel (Abraxane® is 100 mg / m 2 (administered once a week) and the effective amount of carboplatin is AUC = 6. Wherein Nab-paclitaxel (Abraxane®) is administered once a week and carboplatin is administered once every 3 weeks, hi some embodiments, Nab-paclitaxel (Abraxane®) and carboplatin In some embodiments, the NSCLC is advanced NSCLC In some embodiments, the method is used as a first line therapy.

In some embodiments for any of the methods, the method of treating NSCLC further comprises radiation. In some embodiments, the method further comprises chest radiation. For example, a method for treating NSCLC in an individual (eg, a human) includes: a) nanoparticles comprising paclitaxel and albumin (particles comprising albumin coated paclitaxel, eg, Nab-paclitaxel (Abraxane® And the like), b) an effective amount of a platinum-based agent (such as carboplatin), and c) radiation (eg, chest radiation). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 20 mg / m 2 to about 60 mg / m 2 (eg, 40 mg / m 2 ) (administered once a week) An effective amount of a platinum-based drug is about AUC = 2 to AUC = 6 (eg, AUC = 2), and chest radiation is about 25 to about 40 fractions (eg, via 3D conformal or intensity modulation methods) About 33 divisions). In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week and a platinum-based agent is administered once a week. In some embodiments, the treatment period is 7 weeks and the chest radiation is performed simultaneously. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously. In some embodiments, a method of treating NSCLC in an individual (eg, a human) comprising: a) a nanoparticle comprising paclitaxel and albumin (a nanoparticle comprising paclitaxel coated with albumin, eg, Nab − Administering an effective amount of a composition comprising paclitaxel (such as Abraxane®); b) an effective amount of a platinum-based agent (such as carboplatin); and c) radiation (eg, chest radiation). The method further includes consolidation therapy. In some embodiments, the consolidation therapy includes an a) a nanoparticle comprising paclitaxel and albumin (eg, a nanoparticle comprising paclitaxel coated with albumin, such as Nab-paclitaxel (Abraxane®), etc.). Administering an effective amount of the composition; and b) an effective amount of a platinum-based agent (such as carboplatin). In some embodiments of consolidation therapy, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (eg, 50 mg / m 2 , 75 mg / m 2 , or 100 mg / m 2) . 2 ) (once weekly) and an effective amount of platinum-based drug is about AUC = 2 to about AUC = 6 (eg, AUC = 3, AUC = 4.5, or AUC = 6) . In some embodiments, a composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week and a platinum-based agent is administered once every three weeks. In some embodiments, consolidation therapy includes two cycles. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC, PS 0-1, and FEV 1> 800 ml. In some embodiments, the platinum-based agent is carboplatin.

As used herein, a method of treating NSCLC in an individual (eg, a human) comprising: a) a nanoparticle comprising paclitaxel and albumin (a nanoparticle comprising paclitaxel coated with albumin, eg, Nab-paclitaxel ( A method is further provided comprising administering an effective amount of the composition comprising Abraxane®), etc.) and b) an effective amount of radiation (eg, chest radiation). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 20 mg / m 2 to about 60 mg / m 2 (eg, 40 mg / m 2 ) (administered once a week) Chest radiation is about 25 to about 40 divisions (eg, about 33 divisions) via 3D conformal or intensity modulation methods. In some embodiments, the treatment period is 7 weeks and the chest radiation is performed simultaneously. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin is administered intravenously. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC, PS 0-1, and FEV 1> 800 ml.

As used herein, a method of treating NSCLC in an individual (eg, a human) comprising: a) a nanoparticle comprising paclitaxel and albumin (a nanoparticle comprising paclitaxel coated with albumin, eg, Nab-paclitaxel ( A method is further provided comprising administering an effective amount of the composition comprising Abraxane®), etc.) and b) an effective amount of radiation (eg, chest radiation). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 20 mg / m 2 to about 60 mg / m 2 (eg, 40 mg / m 2 ) (administered once a week) Chest radiation is about 25 to about 40 divisions (eg, about 33 divisions) via 3D conformal or intensity modulation methods. In some embodiments, the treatment period is 7 weeks and the chest radiation is performed simultaneously. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously. In some embodiments, the composition comprising nanoparticles comprising paclitaxel and albumin is administered intravenously. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA NSCLC and / or stage IIIB NSCLC, PS 0-1, and FEV 1> 800 ml.

  The methods described herein are useful for various aspects of NSCLC treatment. In some embodiments for any of the methods, the method is a method of inhibiting cell growth by NSCLC (such as tumor growth by NSCLC) in an individual comprising a) a nanoparticle comprising paclitaxel and albumin And b) administering an effective amount of a platinum-based agent. In some embodiments, at least about 10% (eg, including any of at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) cells Inhibits growth.

  In some embodiments for any of the methods, the method is a method of inhibiting tumor metastasis by NSCLC in an individual comprising: a) an effective amount of a composition comprising nanoparticles comprising a) paclitaxel and albumin And b) administering an effective amount of a platinum-based agent. In some embodiments, at least about 10% (eg, including any of at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) Inhibits. In some embodiments, a method of inhibiting metastasis to a lymph node is provided.

  In some embodiments for any of the methods, the method is a method of reducing the tumor size of NSCLC in an individual comprising: a) an effective amount of a composition comprising nanoparticles comprising a) paclitaxel and albumin And b) administering an effective amount of a platinum-based agent. In some embodiments, the tumor size is at least about 10% (eg, at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%). (Including).

  In some embodiments for any of the methods, the method is a method of prolonging progression free survival of NSCLC in an individual comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin And b) administering an effective amount of a platinum-based agent. In some embodiments, the method provides a period of time to disease progression for any of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. ,Extend.

  In some embodiments for any of the methods, the method is a method of extending the survival of an individual having NSCLC, wherein the individual comprises: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin And b) administering an effective amount of a platinum-based agent. In some embodiments, the method comprises at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 months. Prolongs survival.

  In some embodiments for any of the methods, the method is a method of alleviating one or more symptoms in an individual having NSCLC comprising: a) a nanoparticle comprising paclitaxel and albumin Administering a effective amount of the composition and b) an effective amount of a platinum-based agent.

  In some embodiments for any of the methods, the method is a method of reducing AE and SAE in an individual having NSCLC comprising: a) a composition comprising nanoparticles comprising paclitaxel and albumin B) administering a platinum-based agent, wherein the mitigation results from a step of administering a) Taxol® and b) the platinum-based agent to the individual. Based on a comparison with the resulting AE and SAE.

  In some embodiments for any of the methods described herein, the treatment method results in an objective response (such as a partial response or a complete response).

  In some embodiments for any of the methods described herein, the treatment method results in an improvement in quality of life.

  In some embodiments for any of the methods described herein, individuals diagnosed with or suspected of having NSCLC (eg, humans) can be treated. . In some embodiments, the individual is a human. In some embodiments, the individual is at least either about 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the individual is male. In some embodiments, the individual is female. In some embodiments, the individual has any of the NSCLC types described herein. In some embodiments, the individual exhibits a single lesion. In some embodiments, the individual exhibits multiple lesions. In some embodiments, the individual is resistant to treatment of NSCLC with other agents (non-nanoparticle formulations of taxanes, such as Taxol® or Taxotere®). In some embodiments, an individual is initially responsive to treatment of NSCLC with other agents (non-nanoparticulate formulations of taxanes, such as Taxol® or Taxotere®), but progresses after treatment. To do.

  In some embodiments for any of the methods, the method further comprises administration of an effective amount of an anti-angiogenic agent (eg, an angiogenesis inhibitor). In some embodiments, the anti-angiogenic agent is bevacizumab, sunitinib, or sorafenib tosylate. In some embodiments, the anti-angiogenic agent is bevacizumab. In some embodiments, the effective amount of bevacizumab is about 5 mg / kg to about 15 mg / kg. In some embodiments, the effective amount of bevacizumab is either about 5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 15 mg / kg.

  In some embodiments, a lower amount of each pharmaceutically active compound is used as part of the combination therapy compared to the amount commonly used for individual therapy. In some embodiments, a therapeutic benefit that is the same as or greater than the therapeutic benefit achieved by using any of the individual compounds alone is achieved using combination therapy. In some embodiments, a therapeutically the same or greater therapeutic amount is used in combination therapy with a smaller amount (eg, lower dose or less frequent dosing schedule) of the pharmaceutically active compound than is typically used for individual therapy. Achieve profits. For example, the use of a small amount of a pharmaceutically active compound can result in a reduction in the number, severity, frequency, or duration of one or more side effects associated with the compound.

  The methods described herein have the following objectives: alleviating one or more symptoms of NSCLC, delaying the progression of NSCLC, reducing tumor size in NSCLC patients, Inhibiting, prolonging overall survival, prolonging progression-free survival, preventing or delaying tumor metastasis due to NSCLC, reducing (eg eradicating) tumor metastasis due to existing NSCLC, existing It can be used for any one or more of reducing the occurrence or burden of tumor metastasis due to NSCLC, or preventing recurrence of NSCLC.

  In some embodiments for any of the methods described herein, the individual is a human who exhibits one or more symptoms associated with NSCLC. In some embodiments, the individual is genetically or otherwise predisposed to developing NSCLC (eg, has a risk factor). These risk factors include age, sex, race, diet, history of disease, presence of precursor disease, genetic (eg, genetic) considerations, and environmental exposure (eg, cigarettes, pipes, or Cigarette smoking, passive smoking, radon, arsenic, asbestos, chromic acid, chloromethyl ether, nickel, polycyclic aromatic hydrocarbons, radon daughters, other drugs, or exposure to air pollution) However, it is not limited to these. In some embodiments, individuals at risk for NSCLC include, for example, individuals with relatives who have experienced NSCLC, and individuals whose risk is determined by analyzing genetic or biochemical markers. included.

  A method of treating NSCLC in an individual comprising the steps of: a) administering an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum-based agent, , (I) squamous cell carcinoma, (ii) differential levels of caveolin-1 (CAV1), (iii) differential levels of SPARC, (iv) differential levels of hypoxia markers, (v) tumor acidity Degree difference, (vi) difference in level of gp60, (vii) difference in level of thymidylate synthase (TS), (viii) difference in level of S phase kinase related protein (Skp2), (ix) single base Polymorphism (SNP) loss of heterozygosity (LOH), (x) Kras mutation, (xi) methylation of promoter region of tumor-related genes One or more selected from the group consisting of different and (xii) albumin uptake (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9) There is also provided a method based on NSCLC having any of 10, 11 or 12 features.

  As used herein, NSCLC indicates (a) squamous cell carcinoma, (b) differential levels of caveolin-1 (CAV1), (c) differential levels of SPARC, (d) levels of hypoxia markers. Difference, (e) difference in level of tumor acidity, (f) difference in level of gp60, (g) difference in level of thymidylate synthase (TS), (h) level of S-phase kinase-related protein (Skp2) Difference, (i) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (j) difference of Kras mutation, (k) difference in methylation of promoter region of tumor-associated gene, and (l ) One or more selected from the group consisting of differences in albumin uptake (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11) Either one or twelve A method for treating NSCLC in an individual when known to have the following characteristics: i) comprising an effective amount of the composition comprising i) nanoparticles comprising paclitaxel and albumin, and ii) effective Further provided is a method comprising administering an amount of a platinum-based agent.

  Also herein, (a) selecting individuals with NSCLC, wherein NSCLC is (i) squamous cell carcinoma, (ii) caveolin-1 (CAV1) level difference, (iii) Differences in levels of SPARC, (iv) differences in levels of hypoxia markers, (v) differences in levels of tumor acidity, (vi) differences in levels of gp60, (vii) levels of thymidylate synthase (TS) Differences, (viii) differences in levels of S phase kinase-related protein (Skp2), (ix) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (x) differences in Kras mutation, (xi) One or more selected from the group consisting of :) a difference in methylation of the promoter region of a tumor-associated gene, and (xii) a difference in albumin uptake (eg, 1, 2 (3), 4, 5, 6, 7, 8, 9, 9, 10, 11 or 12), and (b) in this way Also provided is a method of treating NSCLC comprising: i) administering an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin to a selected individual, and ii) administering an effective amount of a platinum-based agent. .

  In the present specification, a method for evaluating whether or not a treatment is effective for an individual having NSCLC, comprising: (a) a squamous cell carcinoma; (b) a difference in the level of caveolin-1 (CAV1); ) SPARC level difference, (d) hypoxia marker level difference, (e) tumor acidity level difference, (f) gp60 level difference, (g) thymidylate synthase (TS) level (H) differences in levels of S phase kinase-related protein (Skp2), (i) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (j) differences in Kras mutation, ( k) one or more of NSCLC selected from the group consisting of, for example, a difference in the methylation of the promoter region of a tumor-related gene, and (1) a difference in albumin uptake (eg, 1, 2, 3, 4, 5 pieces 1, 7, 8, 9, 10, 11, or 12), wherein one or more of the NSCLC features is an individual Also provided is a method wherein the treatment is effective and the treatment comprises i) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin and ii) an effective amount of a platinum-based agent.

  In addition, herein, a method for identifying an individual with NSCLC that is likely to respond to treatment comprising a) a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent. (A) (i) Squamous cell carcinoma, (ii) Caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) Hypoxia marker level difference, (V) a difference in the level of tumor acidity, (vi) a difference in the level of gp60, (vii) a difference in the level of thymidylate synthase (TS), (viii) a difference in the level of S-phase kinase-related protein (Skp2), (Ix) Loss of heterozygosity (LOH) of single nucleotide polymorphism (SNP), (x) Difference of Kras mutation, (xi) Methylation of promoter region of tumor-related gene One or more of NSCLC (eg, 1, 2, 3, 4, 5, 6, 7; selected from the group consisting of: Evaluating the characteristics of any of 8, 9, 10, 11 or 12), and (B) (i) squamous cell carcinoma, (ii) caveolin-1 (CAV1) level (Iii) SPARC level differences, (iv) hypoxia marker level differences, (v) tumor acidity level differences, (vi) gp60 level differences, (vii) thymidylate synthase (TS) difference in level, (viii) difference in level of S phase kinase-related protein (Skp2), (ix) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (x) Kras Mutation differences, identifying an individual having one or more characteristics of NSCLC selected from the group consisting of: xi) a difference in the methylation of the promoter region of a tumor-associated gene, and (xii) a difference in albumin uptake. Is provided.

  Also provided herein is a method of marketing a combination therapy comprising a) a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent for use in a subpopulation of NSCLC individuals. (Ii) squamous cell carcinoma, (ii) caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) hypoxia marker level difference, (v) tumor (Vi) differences in levels of acidity, (vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) differences in levels of S-phase kinase-related protein (Skp2), (ix) one Loss of heterozygosity (LOH) in nucleotide polymorphism (SNP), (x) Difference in Kras mutation, (xi) Methylation of promoter region of tumor-related gene One or more selected from the group consisting of differences and (xii) albumin uptake differences (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9) Informing the target customer about the use of combination therapy to treat a sub-population of individuals characterized by a sub-population of individuals with NSCLC characteristics (any of 10, 11, or 12) A method is also provided.

  In some embodiments for any of the methods, one or more features of the NSCLC are one, two, three, four, five, six, seven, eight of the NSCLC. , 9, 10, 11 or 12 features. In some embodiments, the one or more features include, for example, at least two or more features, at least three or more features, at least four or more features, or at least five or more features. For example, in some embodiments, NSCLC is characterized by differential levels of CAV-1 and squamous cell carcinoma. In some embodiments, NSCLC is characterized by differential levels of CAV-1, squamous cell carcinoma, and differential levels of SPARC. In some embodiments, NSCLC is characterized by differences in levels of CAV-1, squamous cell carcinoma, differences in levels of SPARC, and differences in levels of hypoxia markers. In some embodiments, the NSCLC comprises (i) squamous cell carcinoma, (ii) differential levels of caveolin-1 (CAV1), (iii) differential levels of SPARC, (iv) hypoxia markers Level difference, (v) level of tumor acidity, (vi) level difference of gp60, (vii) level difference of thymidylate synthase (TS), (viii) of S phase kinase related protein (Skp2) Level differences, (ix) loss of heterozygosity for single nucleotide polymorphisms (SNPs) (LOH), (x) differences in Kras mutations, (xi) differences in the methylation of promoter regions of tumor-related genes, and (Xii) Characterized by differences in albumin uptake.

  Differences in levels of tumor acidity can be evidenced, for example, by differences in levels of carbonic anhydrase 9 (CA-9) and / or differences in levels of LDH (eg, LDH-5).

  The difference in the level of hypoxia marker is evidenced by, for example, a difference in the level of HIF-1α, a difference in the level of HIF-2α, and / or a difference in the level of differentiated embryo chondrocyte expression gene 1 (DEC-1). sell.

  In some embodiments, one or more features of NSCLC include differences in levels of SPARC. SPARC (Secreted Protein, Acidic and Rich in Cysteine) is a matrix cell protein that is up-regulated in multiple invasive cancers. Porter et al. Histochem. Cytochem. 1995; 43: 791. The human SPARC gene encodes a 303 amino acid SPARC protein, while mature SPARC is a 285 amino acid glycoprotein. After cleavage of the signal sequence, a secreted form of 32 kD is generated that migrates to 43 kD in SDA-PAGE for glycosylation. In some embodiments, the level difference is determined in tumor tissue, normal tissue adjacent to the tumor, normal tissue distal to the tumor, or peripheral blood lymphocytes. In some embodiments, drug uptake capacity is based on SPARC levels in the tumor stroma.

  In some embodiments for any of the methods, the level difference is determined in tumor tissue, normal tissue adjacent to the tumor, normal tissue distal to the tumor, or peripheral blood lymphocytes.

  A “level difference” or “difference” applied to a gene is a variation in the sequence of the nucleic acid, methylation state or degree of methylation, or production of a protein product encoded by the nucleic acid or gene transcribed from the gene. May point. In some embodiments, a gene that is differentially expressed is overexpressed (highly expressed) or underexpressed (lowly expressed) compared to the expression level of normal or control cells, a given patient population, or an internal control. Expression). In some embodiments, the difference is about 1.5 times, about 2.0 times, about 2.5 times, about 3.0 times, about 5.0 times, about 5.0 times the level of expression detected in the control sample. Either 10 times, about 50 times, or about 100 times. In some embodiments, the difference is about 1.5 times, about 2.0 times, about 2.5 times, about 3.0 times less than the expression level detected in the control sample. , About 1 / 5.0, about 1/10, about 1/50, or about 1/100. In some embodiments, there is a nucleotide sequence in a cell or tissue that is expressed in a cell or tissue when silent in a control cell or not expressed in a cell or tissue when expressed in a control cell. .

  In some embodiments, the expression level of a gene of interest is measured for a given patient population, the median expression level of this gene for this population is determined, and the expression level of the same gene for a single patient Is compared to the median expression level for a given patient population. For example, if it is determined that the expression level of a gene of interest for a single patient is above the median expression level of the patient population, the patient is determined to be highly expressing the gene of interest. Alternatively, if the expression level of a gene of interest for a single patient is determined to be below the median expression level of the patient population, the patient is determined to underexpress the gene of interest. In some embodiments, a single patient has NSCLC and the patient population does not have cancer (ie is normal). In some embodiments, a single patient has one histological type of NSCLC (eg, squamous cell carcinoma) and the patient population has a second histological type of NSCLC (eg, Adenocarcinoma). In some embodiments, the single patient and patient population have the same histological type of NSCLC (eg, squamous cell carcinoma).

  In performing this method, the sample is a patient sample containing tumor tissue, normal tissue adjacent to the tumor, normal tissue distal to the tumor, or peripheral blood lymphocytes. The sample nucleic acid used in the methods described above can be obtained from any cell type or tissue of the subject. For example, a body fluid (eg, blood) of a subject can be obtained by a known technique (eg, venipuncture). Alternatively, the test can be performed on a dry sample (eg, hair or skin).

  In some embodiments, the method includes isolating a sample containing the genetic material to be examined. In some embodiments, the method includes determining a level difference in situ. Thus, the methods of the present application are not limited by requiring isolation of genetic material prior to analysis.

  These methods for identifying expression levels are not limited by the technique used to identify the expression level of the gene of interest. The nucleic acid level (RNA level or DNA level) or protein level of the gene of interest can be measured. Methods in the art for measuring gene expression and / or determining sequences to detect polymorphisms are well known in the art, including immunological assays, nuclease protection assays, Northern blots, in situ high Hybridization, ELISA, reverse transcriptase polymerase chain reaction (RT-PCR), real-time polymerase chain reaction, sequencing by EST (expressed sequence tag), cDNA microarray hybridization, or gene chip analysis, subtractive cloning, SAGE (Serial Analysis of Gene Expression, MPSS (Massive Parallel Signature Sequencing), and SBS (Se uncing-By-Synthesis) include but are not limited thereto. It is also possible to perform a diagnostic procedure directly in situ on tissue sections (fixed sections and / or frozen sections) of patient tissue obtained by biopsy or resection.

  Amplification of a polynucleotide includes methods such as PCR, ligation amplification (or ligase chain reaction, LCR), and amplification. These methods are known in the art and are widely practiced. In general, PCR procedures involve (i) sequence specific hybridization of specific genes and primers in a DNA sample (or library), (ii) multiple rounds of annealing, extension, and denaturation using DNA polymerase. A gene amplification method is described that includes subsequent amplification, as well as (iii) screening PCR products for bands of the correct size. The primer used is an oligonucleotide having a length and appropriate sequence sufficient to cause the initiation of polymerization. That is, each primer is specifically designed to be complementary to each strand of the genomic locus to be amplified.

  Reagents and hardware for performing PCR are commercially available. Primers useful for amplifying sequences derived from a particular gene region are preferably complementary to and specifically hybridize to sequences in the target region or its adjacent regions. The nucleic acid sequence produced by amplification can be sequenced directly. Alternatively, the amplified sequence (s) can be cloned and sequenced. Methods in the art for the direct cloning and sequence analysis of enzymatically amplified genomic segments are known.

  In some embodiments for any of the methods herein, the method comprises a measurable reduction in tumor size, a measurable reduction in evidence of disease or disease progression, complete response, partial response, disease stability. Resulting in increased progression-free survival or prolonged progression-free survival, or increased overall survival or prolonged overall survival. In some embodiments for any of the above methods, the likelihood of being successful in the patient is a measurable reduction in tumor size, a measurable reduction in evidence of disease or disease progression, It is manifested by complete response, partial response, disease stability, increased progression-free survival or prolonged progression-free survival, increased overall survival or prolonged overall survival. In some embodiments, at least about 10% (eg, including any of at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) cells Inhibits growth. In some embodiments, at least about 10% (eg, including any of at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) Inhibits. In some embodiments, a method of inhibiting metastasis to a lymph node is provided. In some embodiments, the tumor size is at least about 10% (eg, at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%). (Including). In some embodiments, the method extends progression-free survival for any of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. . In some embodiments, the method comprises at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 months. Prolong progression-free survival. In some embodiments, the method comprises at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 months. Prolongs survival.

  In some embodiments for any of the methods described herein, the method results in an improvement in quality of life.

  The methods herein are applicable to multiple histological types of NSCLC. NSCLC is a squamous cell carcinoma (ie epidermoid carcinoma), large cell carcinoma, adenocarcinoma, adenosquamous carcinoma, polymorphic element, sarcoma-like element, or cancer with sarcoma element, carcinoid It can be a tumor or a salivary gland cancer. In some embodiments, the NSCLC is a squamous cell cancer. In some embodiments, the squamous cell carcinoma is papillary squamous cell carcinoma, clear cell squamous cell carcinoma, small cell squamous cell carcinoma, or basal squamous cell carcinoma. In some embodiments, the NSCLC is a glandular cancer. In some embodiments, the adenocarcinoma is acinar cancer, papillary cancer, bronchoalveolar cancer (eg, non-mucous cell type, mucous cell type, mucous cell type and non-mucous cell type) Mixed or undefined cell type bronchoalveolar carcinoma), solid adenocarcinoma with mucus, adenocarcinoma with mixed subtype, fully differentiated fetal adenocarcinoma, mucinous (colloidal) Adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, or clear cell glandular cancer. In some embodiments, the large cell cancer is a large cell neuroendocrine cancer, mixed large cell neuroendocrine cancer, basal cell carcinoma, lymphoepithelioma-like cancer, clear cell carcinoma, or rhabdoid Large cell cancer with phenotype. In some embodiments, the cancer with a polymorphic element, sarcoma-like element, or sarcoma element is cancer with spindle cells and / or giant cells, spindle cell cancer, giant cell cancer, carcinosarcoma Or lung blastoma. In some embodiments, the type of salivary adenocarcinoma is mucinous epidermoid cancer or adenoid cyst cancer.

  NSCLC of any of the methods herein is a latent tumor, a stage 0 tumor, a stage I tumor (stage IA (T1, N0, M0) tumor, or stage IB (T2, N0) , M0) tumors), stage II tumors (stage IIA (T1, N1, M0) tumors, and stage IIB (T2, N1, M0) tumors), stage IIIA tumors (T1, N2) , M0, T2, N2, M0, T3, N1, M0, or T3, N2, M0), stage IIIB tumor (any T, N3, M0, or T4, any N, M0), or stage It can be an IV tumor (any T, any N, M1). In some embodiments for any of the methods described herein, the NSCLC is early NSCLC, non-metastatic NSCLC, primary NSCLC, advanced NSCLC, locally advanced NSCLC, metastatic NSCLC, remission phase NSCLC or recurrent NSCLC. In some embodiments, the NSCLC is resectable local NSCLC, unresectable local NSCLC, or unresectable NSCLC.

  The methods provided herein can be practiced in an adjuvant setting. In some embodiments, the method is performed in a neoadjuvant situation. That is, the method can be performed before primary / root treatment. In some embodiments, this treatment is used to treat a previously treated individual. Any of the treatment methods provided herein can be used to treat an individual who has not been previously treated. In some embodiments, the method is used as a first line therapy. In some embodiments, the method is used as a second line therapy.

  In some embodiments for any of the methods described herein, the composition comprises nanoparticles comprising paclitaxel and albumin (such as human serum albumin), and the paclitaxel in the nanoparticles comprises albumin. It is coated with. In some embodiments, the average particle size of the nanoparticles in the composition is about 200 nm or less (such as less than about 200 nm). In some embodiments, the composition comprises Nab-paclitaxel (Abraxane®). In some embodiments, the composition is Nab-paclitaxel (Abraxane®). In some embodiments, the nanoparticle composition and the platinum-based agent have a synergistic effect on the treatment of NSCLC.

  Platinum-based agents covalently bind to DNA, crosslink strands, inhibit DNA synthesis, and / or inhibit transcripts. In some embodiments, the platinum-based formulation is carboplatin, cisplatin, or oxaliplatin. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cisplatin.

In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 40 to about 125 mg / m 2 , or about 50 to about 125 mg / m 2 (eg, 40 mg / m 2 , 50 mg / M 2 , 60 mg / m 2 , 75 mg / m 2 , or 100 mg / m 2 ) and an effective amount of a platinum-based drug is from about AUC = 2 to about AUC = 6 (eg, AUC = 2, AUC = 3, AUC = 4.5, or AUC = 6). In some embodiments, an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week, and an effective amount of a platinum-based agent is administered every 3 weeks. In some embodiments, an effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week and an effective amount of a platinum-based agent is administered once a week. In some embodiments, the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is about 50 to about 125 mg / m 2 (administered once a week) and the effective amount of the platinum-based agent is about AUC = 2 to about AUC = 6 (once administered every 3 weeks). In some embodiments, the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is about 40 to about 125 mg / m 2 (administered once a week) and the effective amount of the platinum-based agent is about AUC = 2 to about AUC = 6 (administered once a week). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 100 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 6 ( Once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 75 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 4. 5 (once every 3 weeks). In some embodiments, an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 50 mg / m 2 (administered once a week) and an effective amount of a platinum-based drug is about AUC = 3 ( Once every 3 weeks). In some embodiments, the effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is about 40 mg / m 2 (once weekly) and the effective amount of a platinum-based drug is AUC = 2 (weeks Once). In some embodiments, the paclitaxel nanoparticle composition and / or the platinum-based agent is administered intravenously. In some embodiments, the paclitaxel nanoparticle composition and the platinum-based agent are administered intravenously.

  In some embodiments for any of the methods, the composition comprising nanoparticles comprising paclitaxel and albumin is administered without any pre-medication of steroids and / or without G-CSF prophylaxis. .

  In some embodiments for any of the methods, the method further comprises administration of an effective amount of an anti-angiogenic agent (eg, an angiogenesis inhibitor). In some embodiments, the anti-angiogenic agent is bevacizumab, sunitinib, or sorafenib tosylate. In some embodiments, the anti-angiogenic agent is bevacizumab. In some embodiments, the effective amount of bevacizumab is about 5 mg / kg to about 15 mg / kg. In some embodiments, the effective amount of bevacizumab is either about 5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 15 mg / kg.

Prostate cancer The present invention is a method of treating prostate cancer in an individual (eg, a human) comprising: a) an effective amount of a composition comprising nanoparticles comprising docetaxel and albumin; and b) an effective amount of A method is provided comprising administering a steroid (eg, prednisone). The present invention relates to a method of treating prostate cancer in an individual (eg, a human) comprising: a) an effective amount of a composition comprising nanoparticles comprising docetaxel and albumin; and b) an effective amount of a steroid (eg, , Prednisone). In some embodiments, a method of treating prostate cancer in an individual (eg, a human), wherein the individual comprises a) an effective amount of a composition comprising nanoparticles comprising albumin coated docetaxel; and b). A method is provided comprising administering an effective amount of a steroid (eg, prednisone). In some embodiments, a method of treating prostate cancer in an individual (eg, a human) comprising: a) an effective amount of a composition comprising nanoparticles comprising docetaxel and albumin comprising: A method is provided comprising administering a composition wherein the average size of nanoparticles in the article is about 200 nm or less, and b) an effective amount of a steroid (eg, prednisone). In some embodiments, a method of treating prostate cancer in an individual (e.g., a human) comprising: a) an effective amount of a composition comprising nanoparticles comprising a) docetaxel coated with albumin; A method is provided comprising administering a composition wherein the average size of the nanoparticles in the nanoparticle composition is about 200 nm or less, and b) an effective amount of a steroid (eg, prednisone). In some embodiments, a method of treating prostate cancer in an individual (eg, a human) comprising: a) an effective amount of Nab-docetaxel (the average size of the nanoparticles in the nanoparticle composition is about 200 nm). And b) administering an effective amount of a steroid (e.g., prednisone).

  Also, a method of treating prostate cancer in an individual, wherein the individual is administered a) an effective amount of a composition comprising nanoparticles comprising docetaxel and albumin, and b) an effective amount of a steroid (eg, prednisone). Treatment comprising: (i) adenocarcinoma, (ii) caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) gp60 level difference, and (v) Also provided is a method based on prostate cancer having one or more characteristics selected from the group consisting of differences in albumin uptake. In some embodiments, a method of treating prostate cancer in an individual comprising: a) an effective amount of a composition comprising nanoparticles comprising docetaxel coated with albumin; and b) an effective amount of a steroid ( For example, prednisone), wherein the treatment comprises (i) adenocarcinoma, (ii) caveolin-1 (CAV1) level differences, (iii) SPARC level differences, (iv) gp60 levels Methods are provided based on prostate cancer having one or more characteristics selected from the group consisting of a difference in level and (v) a difference in albumin uptake. In some embodiments, a method of treating prostate cancer in an individual comprising: a) an effective amount of a composition comprising a) nanoparticles comprising docetaxel and albumin, wherein the nanoparticles in the nanoparticle composition Administering a composition having an average size of about 200 nm or less, and b) an effective amount of a steroid (eg, prednisone), wherein the treatment comprises (i) adenocarcinoma, (ii) caveolin-1 ( A prostate having one or more characteristics selected from the group consisting of: a difference in the level of CAV1), (iii) a difference in the level of SPARC, (iv) a difference in the level of gp60, and (v) a difference in albumin uptake. A method based on this is provided. In some embodiments, a method of treating prostate cancer in an individual comprising: a) an effective amount of a composition comprising a) nanoparticles comprising docetaxel coated with albumin, wherein the individual comprises in the nanoparticle composition Administering a composition wherein the nanoparticles have an average size of about 200 nm or less, and b) an effective amount of a steroid (eg, prednisone), the treatment comprising (i) adenocarcinoma, (ii) caveolin One or more characteristics selected from the group consisting of:-1 (CAV1) level difference, (iii) SPARC level difference, (iv) gp60 level difference, and (v) albumin uptake difference A method based on having prostate cancer is provided. In some embodiments, a method of treating prostate cancer in an individual comprising the steps of: a) administering an effective amount of Nab-docetaxel and b) an effective amount of a steroid (eg, prednisone). Treatment of (i) adenocarcinomas, (ii) differences in caveolin-1 (CAV1) levels, (iii) differences in SPARC levels, (iv) differences in gp60 levels, and (v) albumin uptake Methods are provided based on prostate cancer having one or more characteristics selected from the group consisting of differences.

  Also disclosed herein is a method of treating prostate cancer comprising the steps of: (a) selecting an individual having prostate cancer, wherein the prostate cancer comprises (i) adenocarcinoma, (ii) caveolin. One or more characteristics selected from the group consisting of:-1 (CAV1) level difference, (iii) SPARC level difference, (iv) gp60 level difference, and (v) albumin uptake difference And (b) administering to the thus selected individual i) an effective amount of a composition comprising nanoparticles comprising docetaxel and albumin, and ii) administering an effective amount of a steroid. Provided. In some embodiments, a method of treating prostate cancer comprising: (a) selecting an individual having prostate cancer, wherein the prostate cancer is (i) an adenocarcinoma; (ii) One or more characteristics selected from the group consisting of: caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) gp60 level difference, and (v) albumin uptake difference And (b) administering to the thus selected individual i) an effective amount of a composition comprising nanoparticles comprising docetaxel coated with albumin; and ii) administering an effective amount of a steroid. A method is provided. In some embodiments, a method of treating prostate cancer comprising: (a) selecting an individual having prostate cancer, wherein the prostate cancer is (i) an adenocarcinoma; (ii) One or more characteristics selected from the group consisting of: caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) gp60 level difference, and (v) albumin uptake difference And (b) an effective amount of the composition comprising i) a nanoparticle comprising docetaxel and albumin to the individual thus selected, wherein the average size of the nanoparticles in the nanoparticle composition is about And ii) administering an effective amount of a steroid that is 200 nm or less. In some embodiments, a method of treating prostate cancer comprising: (a) selecting an individual having prostate cancer, wherein the prostate cancer is (i) an adenocarcinoma; (ii) One or more characteristics selected from the group consisting of: caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) gp60 level difference, and (v) albumin uptake difference And (b) an effective amount of the composition comprising nanoparticles comprising docetaxel coated with albumin, and (b) an individual selected in this manner, wherein the average of the nanoparticles in the nanoparticle composition A composition having a size of about 200 nm or less, and ii) administering an effective amount of a steroid. In some embodiments, a method of treating prostate cancer comprising: (a) selecting an individual having prostate cancer, wherein the prostate cancer is (i) an adenocarcinoma; (ii) One or more characteristics selected from the group consisting of: caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (iv) gp60 level difference, and (v) albumin uptake difference And (b) administering to the thus selected individual i) an effective amount of Nab-docetaxel, and ii) an effective amount of a steroid.

  In some embodiments for any of the methods, the one or more characteristics of prostate cancer include one, two, three, four, or five characteristics of prostate cancer. . In some embodiments, the one or more features include, for example, at least two or more features, at least three or more features, or at least four or more features. For example, in some embodiments, prostate cancer is characterized by a difference in the level of CAV-1. In some embodiments, prostate cancer is characterized by differences in levels of CAV-1 and differences in levels of gp60. In some embodiments, prostate cancer is characterized by differential levels of caveolin-1 (CAV1), differential levels of SPARC, differential levels of gp60, and differential albumin uptake.

  In some embodiments for any of the methods, the prostate cancer is a glandular cancer. In some embodiments, the prostate cancer is a sarcoma, neuroendocrine tumor, small cell cancer, ductal cancer, or lymphoma. A method of treating prostate cancer in any of the four stages of A, B, C, or D by the Jewett staging system is provided. In some embodiments, the prostate cancer is stage A prostate cancer (cannot be detected by rectal screening). In some embodiments, the prostate cancer is stage B prostate cancer (the tumor is involved in more tissue within the prostate and can be detected by rectal examination or with high PSA levels) As revealed by a biopsy done for them). In some embodiments, the prostate cancer is stage C prostate cancer (the cancer has spread to nearby tissues outside the prostate). In some embodiments, the prostate cancer is stage D prostate cancer.

  In some embodiments for any of the methods, the prostate cancer can be androgen independent prostate cancer (AIPC). In some embodiments, the prostate cancer can be an androgen-dependent prostate cancer. In some embodiments, prostate cancer can be refractory to hormone therapy. In some embodiments, prostate cancer can be substantially refractory to hormone therapy. In some embodiments, the individual has a gene, gene mutation, or polymorphism associated with prostate cancer (eg, RNASEL / HPC1, ELAC2 / HPC2, SR-A / MSR1, CHEK2, BRCA2, PON1). , OGG1, MIC-1, TLR4, and / or PTEN), or a human having one or more additional copies of a gene associated with prostate cancer.

  In some embodiments for any of the methods described herein, the prostate cancer is early prostate cancer, non-metastatic prostate cancer, primary prostate cancer, advanced prostate cancer, Locally advanced prostate cancer, metastatic prostate cancer, remission prostate cancer, or recurrent prostate cancer. In some embodiments, the prostate cancer is resectable local prostate cancer, unresectable local prostate cancer, or unresectable prostate cancer.

  The methods provided herein can be practiced in an adjuvant setting. In some embodiments, the method is performed in a neoadjuvant situation. That is, the method can be performed before primary / root treatment. In some embodiments, this treatment is used to treat a previously treated individual. Any of the treatment methods provided herein can be used to treat an individual who has not been previously treated. In some embodiments, the method is used as a first line therapy. In some embodiments, the method is used as a second line therapy.

  In some embodiments for any of the methods described herein, the composition comprises nanoparticles comprising docetaxel and albumin (such as human serum albumin), and the docetaxel in the nanoparticles is albumin. It is coated with. In some embodiments, the average particle size of the nanoparticles in the composition is about 200 nm or less (such as less than about 200 nm). In some embodiments, the composition comprises Nab-docetaxel. In some embodiments, the composition is Nab-docetaxel. In some embodiments, the docetaxel nanoparticle composition and the steroid have a synergistic effect on the treatment of prostate cancer. In some embodiments, the steroid is prednisone.

In some embodiments for any of the methods described herein, an effective amount of a composition comprising nanoparticles comprising docetaxel and albumin is about 30 mg / m 2 to about 200 mg / m 2 ( For example, 60 mg / m 2 , 75 mg / m 2 , or 100 mg / m 2 ) and an effective amount of steroid is from about 2.5 mg to about 20 mg (eg, 2.5 mg, 5 mg, or 10 mg). In some embodiments for any of the methods described herein, an effective amount of a composition comprising nanoparticles comprising docetaxel and albumin is administered once every three weeks to provide an effective amount of a steroid Is administered twice daily. In some embodiments, the effective amount of the composition comprising nanoparticles comprising docetaxel and albumin is about 30 to about 200 mg / m 2 (administered once every 3 weeks) and the effective amount of steroid is about 2. 5 to about 20 mg (administered twice daily). In some embodiments, the effective amount of the composition comprising nanoparticles comprising docetaxel and albumin is about 75 mg / m 2 (administered once every 3 weeks) and the effective amount of steroid is about 5 mg (twice daily). Administration). In some embodiments, the docetaxel nanoparticle composition is administered intravenously. In some embodiments, the steroid is administered orally. In some embodiments, the composition comprising nanoparticles comprising docetaxel and albumin and the steroid are administered sequentially, co-administered, or co-administered.

Thus, for example, in some embodiments, a method of treating prostate cancer in an individual comprising: a) about 30 mg / m 2 to about 200 mg / m 2 (eg, 60 mg / m 2 , 75 mg / m 2 or 100 mg / m 2 ) nanoparticles comprising docetaxel and albumin (such as nanoparticles comprising docetaxel coated with albumin, such as Nab-docetaxel), and b) from about 2.5 mg to about 20 mg (eg, A method is provided comprising administering 2.5 mg, 5 mg, or 10 mg) of a steroid (such as prednisone). In some embodiments, a method of treating prostate cancer in an individual comprising: a) about 30 mg / m 2 to about 200 mg / m 2 (eg, 60 mg / m 2 , 75 mg) once every 3 weeks. / M 2 , or 100 mg / m 2 ) nanoparticles comprising docetaxel and albumin (such as nanoparticles comprising albumin-coated docetaxel, eg, Nab-docetaxel), and b) about 2.5 mg to twice daily A method is provided comprising administering about 20 mg (eg, 2.5 mg, 5 mg, or 10 mg) of a steroid (such as prednisone). In some embodiments, a method of treating prostate cancer in an individual comprising: a) about 30 mg / m 2 to about 200 mg / m 2 (eg, 60 mg / m 2 , 75 mg) once every 3 weeks. / M 2 , or 100 mg / m 2 ) nanoparticles containing docetaxel and albumin (such as nanoparticles containing albumin-coated docetaxel, eg, Nab-docetaxel), b) about twice daily A method is provided comprising orally administering 2.5 mg to about 20 mg (eg, 2.5 mg, 5 mg, or 10 mg) of a steroid (such as prednisone).

  In some embodiments for any of the methods described herein, an individual (eg, a human) who has been diagnosed or suspected of having prostate cancer is treated. can do. In some embodiments, the individual is a human. In some embodiments, the individual is at least either about 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the individual is male. In some embodiments, the individual has any of the types of prostate cancer described herein. In some embodiments, the individual exhibits a single lesion. In some embodiments, the individual exhibits multiple lesions. In some embodiments, the individual is resistant to treatment of prostate cancer with other agents, such as non-nanoparticle formulations of taxanes, such as Taxol® or Taxotere®. In some embodiments, the individual initially responds to treatment of prostate cancer with other agents (such as non-nanoparticle formulations of taxanes, such as Taxol® or Taxotere®), Progress after treatment.

  In some embodiments, a lower amount of each pharmaceutically active compound is used as part of the combination therapy compared to the amount commonly used for individual therapy. In some embodiments, a therapeutic benefit that is the same as or greater than the therapeutic benefit achieved by using any of the individual compounds alone is achieved using combination therapy. In some embodiments, a therapeutically the same or greater therapeutic amount is used in combination therapy using a smaller amount (eg, lower dose or less frequent dosing schedule) of the pharmaceutically active compound than is typically used for monotherapy. Achieve profits. For example, the use of a small amount of a pharmaceutically active compound can result in a reduction in the number, severity, frequency, or duration of one or more side effects associated with the compound.

  The methods described herein are for the following purposes: alleviating one or more symptoms of prostate cancer, slowing prostate cancer progression, reducing tumor size in prostate cancer patients Inhibiting prostate cancer growth, prolonging overall survival, prolonging progression-free survival, preventing or delaying metastasis from prostate cancer, metastasis from existing prostate cancer For any one or more of reducing (e.g. eradicating), reducing the occurrence or burden of tumor metastasis from existing prostate cancer, or preventing recurrence of prostate cancer it can.

Dosage and Methods of Nanoparticle Composition Administration Although this section focuses on methods of treating NSCLC using nanoparticle compositions comprising paclitaxel, this description also applies to other cancers described herein. It should be understood that this also applies to treatment, eg, treatment of prostate cancer using nanoparticles comprising docetaxel.

  The dose of paclitaxel nanoparticle composition administered to an individual (such as a human) can vary depending on the specific composition, mode of administration, and type of NSCLC being treated. In some embodiments, the amount of paclitaxel nanoparticle composition and / or the amount of a platinum-based agent (eg, carboplatin) is effective to result in an objective response (such as a partial response or a complete response). . In some embodiments, the amount of paclitaxel nanoparticle composition and / or the amount of platinum-based agent (eg, carboplatin) is sufficient to result in a complete response in the individual. In some embodiments, the amount of paclitaxel nanoparticle composition and / or the amount of platinum-based agent (eg, carboplatin) is sufficient to result in a partial response in the individual. In some embodiments, the amount of paclitaxel nanoparticle composition and the amount of platinum-based agent (eg, carboplatin) is the amount of paclitaxel nanoparticle composition alone, Taxol® alone, platinum-based agent (eg, carboplatin). ) Alone and / or resulting in a higher objective response (such as a partial response or complete response) in an individual compared to a combination of Taxol® and a platinum-based drug (eg, carboplatin). It is enough. The response of the treatment methods described herein to an individual can be determined based on, for example, the RECIST level.

  In some embodiments, the amount of paclitaxel nanoparticle composition and / or the amount of platinum-based agent (eg, carboplatin) is sufficient to prolong the progression-free survival of the individual. In some embodiments, the amount of paclitaxel nanoparticle composition and / or the amount of platinum-based agent (eg, carboplatin) is sufficient to prolong the overall survival of the individual. In some embodiments, the amount of paclitaxel nanoparticle composition and the amount of platinum-based agent (eg, carboplatin) is the amount of paclitaxel nanoparticle composition alone, Taxol® alone, platinum-based agent (eg, carboplatin). ) Alone and / or compared to a combination of Taxol® and a platinum-based agent (eg, carboplatin) is sufficient to prolong the progression-free survival of the individual.

  In some embodiments, the amount of paclitaxel nanoparticle composition and / or the amount of platinum-based agent (eg, carboplatin) is a corresponding tumor size, number of NSCLC cells, or tumor in the same subject at the start of treatment. At least about 10%, 20%, 30%, 40%, 50%, 60%, 70% compared to the growth rate or corresponding activity in other subjects not receiving this treatment , 80%, 90%, 95%, or 100%, an amount sufficient to reduce the size of the tumor, reduce the number of cancer cells, or reduce the growth rate of the tumor It is. In some embodiments, the amount of paclitaxel nanoparticle composition and the amount of platinum-based agent (eg, carboplatin) is the amount of paclitaxel nanoparticle composition alone, Taxol® alone, platinum-based agent (eg, carboplatin). ) Alone and / or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70 compared to a combination of Taxol® and a platinum-based drug (eg, carboplatin). %, 80%, 90%, 95%, or 100% to reduce the size of the tumor, reduce the number of cancer cells, or the growth rate of the tumor at the start of treatment Is sufficient to reduce The magnitude of this effect can be measured using standard methods.

  In some embodiments, the amount of paclitaxel in the nanoparticle composition is at a level that is lower than a level that induces a toxic effect (ie, an effect that exceeds a clinically acceptable toxicity level) or the nanoparticle composition. Is administered to an individual at a level that can control or tolerate potential side effects.

  In some embodiments, the amount of paclitaxel nanoparticle composition and / or the amount of platinum-based agent (eg, carboplatin) is close to the maximum tolerated dose (MTD) of the composition according to the same dosage regime. In some embodiments, the amount of the composition is greater than any of about 80%, 90%, 95%, or 98% of the MTD.

  In some embodiments, the amount of paclitaxel in the nanoparticle composition is in the following ranges: about 0.1 mg to about 500 mg, about 0.1 mg to about 2.5 mg, about 0.5 to about 5 mg, about 5 to about 5 mg. About 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg About 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about Included in any of 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg. In some embodiments, the amount of paclitaxel in an effective amount of the nanoparticle composition (eg, unit dosage form) ranges from about 5 mg to about 500 mg, such as from about 30 mg to about 300 mg or from about 50 mg to about 200 mg. In some embodiments, the concentration of paclitaxel in the nanoparticle composition is, for example, about 0.1 to about 50 mg / ml, about 0.1 to about 20 mg / ml, about 1 to about 10 mg / ml, about 2 mg / ml. Dilute (about 0.1 mg / ml) or concentrate (about 100 mg / ml), including any of ml to about 8 mg / ml, about 4 to about 6 mg / ml, or about 5 mg / ml. In some embodiments, the concentration of paclitaxel is at least about 0.5 mg / ml, 1.3 mg / ml, 1.5 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml. One of ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 40 mg / ml, or 50 mg / ml.

Exemplary effective amounts of paclitaxel in the nanoparticle composition include at least about 25 mg / m 2 , 30 mg / m 2 , 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 90 mg / m. 2 , 100 mg / m 2 , 120 mg / m 2 , 125 mg / m 2 , 150 mg / m 2 , 160 mg / m 2 , 175 mg / m 2 , 180 mg / m 2 , 200 mg / m 2 , 210 mg / m 2 , 220 mg / m 2 , 250 mg / m 2 , 260 mg / m 2 , 300 mg / m 2 , 350 mg / m 2 , 400 mg / m 2 , 500 mg / m 2 , 540 mg / m 2 , 750 mg / m 2 , 1000 mg / m 2 , or 1080 mg / m Any of m 2 paclitaxel is included, but not limited to. In various embodiments, the composition is less than about 350 mg / m 2, less than 300 mg / m 2, less than 250 mg / m 2, less than 200 mg / m 2, less than 150 mg / m 2, less than 120mg / m 2, 100mg / m encompasses less than 2, less than 90 mg / m 2, less than 50 mg / m 2, or any of 30 mg / m 2 less than paclitaxel. In some embodiments, the amount of paclitaxel per dose is about 25 mg / m 2 , 22 mg / m 2 , 20 mg / m 2 , 18 mg / m 2 , 15 mg / m 2 , 14 mg / m 2 , 13 mg / m m 2 , 12 mg / m 2 , 11 mg / m 2 , 10 mg / m 2 , 9 mg / m 2 , 8 mg / m 2 , 7 mg / m 2 , 6 mg / m 2 , 5 mg / m 2 , 4 mg / m 2 , 3 mg / m 2, 2mg / m 2, or less than any of the 1 mg / m 2. In some embodiments, the effective amount of paclitaxel in the nanoparticle composition is in the following ranges: about 1 to about 5 mg / m 2 , about 5 to about 10 mg / m 2 , about 10 to about 25 mg / m 2 , about 25 to about 50 mg / m 2, about 50 to about 75 mg / m 2, about 75 to about 100 mg / m 2, about 100 to about 125 mg / m 2, about 125 to about 150 mg / m 2, about 150 to about 175 mg / m 2, about 175 to about 200 mg / m 2, about 200 to about 225 mg / m 2, about 225 to about 250 mg / m 2, about 250 to about 300 mg / m 2, about 300 to about 350 mg / m 2 or about, Included in any of 350 to about 400 mg / m 2 . In some embodiments, the effective amount of paclitaxel in the nanoparticle composition is about 20 to about 60 mg / m 2 , about 100 to about 150 mg / m 2 , about 120 mg / m 2 , about 130 mg / m 2 , or about such as 140 mg / m 2, from about 5 to about 300 mg / m 2.

  In some embodiments for any of the above aspects, the effective amount of paclitaxel in the nanoparticle composition is at least about 1 mg / kg, 2.5 mg / kg, 3.5 mg / kg, 5 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg either kg or 60 mg / kg. In various embodiments, an effective amount of paclitaxel in the nanoparticle composition is less than about 350 mg / kg, less than 300 mg / kg, less than 250 mg / kg, less than 200 mg / kg, less than 150 mg / kg, less than 100 mg / kg, 50 mg / kg. <kg, <25 mg / kg, <20 mg / kg, <10 mg / kg, <7.5 mg / kg, <6.5 mg / kg, <5 mg / kg, <3.5 mg / kg, <2.5 mg / kg Or less than 1 mg / kg of paclitaxel.

  Exemplary dosing frequencies for administering paclitaxel nanoparticle compositions include daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week without a break, out of four weeks This includes, but is not limited to, once every three weeks, once every three weeks, once every two weeks, or two of the three weeks. In some embodiments, the paclitaxel nanoparticle composition is about once every two weeks, about once every three weeks, about once every four weeks, about once every six weeks, or every eight weeks. About once. In some embodiments, the paclitaxel nanoparticle composition is any of at least about once, twice, three times, four times, five times, six times, or seven times (ie daily) once a week. Is administered. In some embodiments, the paclitaxel nanoparticle composition is administered once a week. In some embodiments, the interval between each administration is about 6 months, 3 months, 1 month, 20 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days. 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or less than 1 day. In some embodiments, the interval between each administration is between about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. Any one is exceeded. In some embodiments, there is no break during the dosing schedule. In some embodiments, the interval between each administration is about 1 week or less.

In some embodiments, the dosing frequency is once every two days, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, And over 11 times. In some embodiments, the dosing frequency is once every two days and spans five times. In some embodiments, paclitaxel in the nanoparticle composition is administered for at least 10 days, the interval between each administration is about 2 days or less, and the dose of paclitaxel in each administration is about 0.25 mg / m 2 to about 25 mg / m 2, such as about 20 mg / m 2 to about 60 mg / m 2 or about 25 mg / m 2 to about 50 mg / m 2,, about 0.25 mg / m 2 to about 250 mg / m 2, about 0 .25 mg / m 2 to about 150 mg / m 2 , about 0.25 mg / m 2 to about 75 mg / m 2 .

  Administration of the paclitaxel nanoparticle composition can be extended over a long period of time, such as from about 1 month to about 7 years. In some embodiments, the paclitaxel nanoparticle composition is at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, Administer over either period of 72 or 84 months.

In some embodiments, the dose of paclitaxel in the nanoparticle composition may be in the range of 5-400 mg / m 2 when administered on a 3 week schedule and 5 when administered on a once weekly schedule. ~250mg / m 2 (40~100mg / m 2, 50~125mg / m 2, for example, 50 to 100 mg / m 2) in some cases in the range of. For example, the amount of paclitaxel is about 50 to about 125 mg / m 2 (eg, about 100 mg / m 2 ) on a weekly schedule, for example, once a week without holidays.

Other exemplary dosing schedules for administering paclitaxel in a nanoparticulate composition include 100 mg / m 2 weekly without break, 75 mg / m 2 weekly without break, week without break 50 mg / m 2 once a week for 3 weeks out of 4 weeks 100 mg / m 2 once a week for 3 weeks out of 4 weeks, 75 mg / m 2 once a week for 3 weeks, or 3 weeks out of 4 weeks One dose includes 50 mg / m 2 but is not limited to these. The frequency of administration of the composition can be adjusted over the treatment period based on the judgment of the administering physician.

In some embodiments for any of the above aspects, the cumulative dose of paclitaxel in the administered nanoparticle composition is at least about 1000 mg / m 2 , 1100 mg / m 2 , 1200 mg / m 2 , 1300 mg / m 2, includes any of 1400mg / m 2, 1450mg / m 2, 1500mg / m 2, 1600mg / m 2 or 1700 mg / m 2, is. In some embodiments, the cumulative dose of paclitaxel in the nanoparticle composition is about 1000mg / m 2 ~1700mg / m 2 , 1100mg / m 2 ~1600mg / m 2, 1200mg / m 2 ~1600mg / m 2, 1300mg / m 2 ~1600mg / m 2, or at any of 1400mg / m 2 ~1500mg / m 2 .

  In some embodiments, the individual is treated for at least about any one of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles.

  The paclitaxel nanoparticle compositions described herein allow an individual to infuse the paclitaxel nanoparticle composition over an infusion time that is less than about 24 hours. For example, in some embodiments, the paclitaxel nanoparticle composition is about 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or 10 minutes Administer over any infusion period below. In some embodiments, the composition is administered over an infusion period of about 30 minutes.

  In some embodiments, the amount of platinum-based agent (eg, carboplatin) is any of about AUC = 1 to AUC = 10, AUC = 2 to AUC = 8, or AUC = 3 to AUC = 6. It is. In some embodiments, the amount of platinum-based agent (eg, carboplatin) is about AUC = 2, AUC = 2.5, AUC = 3, AUC = 3.5, AUC = 4, AUC = 4.5. , AUC = 5, AUC = 5.5, AUC = 6, AUC = 6.5, or AUC = 7. Exemplary dosing frequencies for administering a platinum-based drug (eg, carboplatin) include daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week without a break. Including, but not limited to, three weeks of the week, once every three weeks, once every two weeks, or two of the three weeks. In some embodiments, the platinum-based agent (eg, carboplatin) is applied about once every two weeks, about once every three weeks, about once every four weeks, about once every six weeks, Or about once every 8 weeks. In some embodiments, the interval between each administration is about 6 months, 3 months, 1 month, 20 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days. 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or less than 1 day. In some embodiments, the interval between each administration is between about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. Any one is exceeded. In some embodiments, there is no break during the dosing schedule. In some embodiments, the interval between each administration is about 1 week or less.

In some embodiments, the dose of a platinum-based agent (eg, carboplatin) is about AUC = 2 to about AUC = 6 (about AUC = 2, AUC = 3, AUC = 4 when administered on a 3 week schedule. .5, or AUC = 6, etc., when administered on a 3 week schedule of 4 weeks, AUC = 2 to about AUC = 6 (about AUC = 2, AUC = 3) , AUC = 4.5, or AUC = 6, etc.). For example, the amount of paclitaxel is about 50 to about 125 mg / m 2 (eg, about 100 mg / m 2 ) on a weekly schedule, for example, once a week without holidays. In some embodiments, the dose of a platinum-based agent (eg, carboplatin) is about AUC = 2 to about AUC = 6 (about AUC = 2, AUC = 3, AUC = 4. 5 or any of AUC = 6).

  The nanoparticle composition and the platinum-based agent (eg, carboplatin) can be administered using the same route of administration or can be administered using different routes of administration. Paclitaxel nanoparticle compositions and / or platinum-based agents (eg, carboplatin) are, for example, intravenous, intraarterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesical, intramuscular. And can be administered to an individual (such as a human) via various routes, including intratracheal route, subcutaneous route, intraocular route, intrathecal route, transmucosal route, and transdermal route. In some embodiments, a paclitaxel nanoparticle composition and / or a sustained release formulation of a platinum-based drug can be used. In some embodiments, the paclitaxel nanoparticle composition and / or a platinum-based agent (eg, carboplatin) is administered intravenously. In some embodiments, the paclitaxel nanoparticle composition and a platinum-based agent (eg, carboplatin) are administered intravenously. In some embodiments, the paclitaxel nanoparticle composition and / or a platinum-based agent (eg, carboplatin) is administered intraportally. In some embodiments, the paclitaxel nanoparticle composition and / or a platinum-based agent (eg, carboplatin) is administered intraarterially. In some embodiments, the paclitaxel nanoparticle composition and / or a platinum-based agent (eg, carboplatin) is administered intraperitoneally. In some embodiments, the paclitaxel nanoparticle composition and / or a platinum-based agent (eg, carboplatin) is administered by inhalation.

  In some embodiments, the paclitaxel nanoparticle composition and a platinum-based agent (eg, carboplatin) are co-administered. When co-administering drugs, the paclitaxel in the nanoparticles and the platinum-based agent are contained in the same composition (eg, a composition comprising both nanoparticles and a platinum-based agent) or separate compositions (Eg, nanoparticles are contained in one composition and platinum-based agents (eg, carboplatin) are contained in another composition).

  In some embodiments, the paclitaxel nanoparticle composition and the platinum-based agent (eg, carboplatin) are administered sequentially. The paclitaxel nanoparticle composition can be administered first, and a platinum-based agent (eg, carboplatin) can be administered first. The paclitaxel nanoparticle composition and the platinum-based drug (eg, carboplatin) are contained in separate compositions, which may be contained in the same package or in different packages. There is also a case.

  In some embodiments, the paclitaxel nanoparticle composition and a platinum-based agent (eg, carboplatin) are administered simultaneously. That is, the administration period of the nanoparticle composition and the administration period of the platinum-based drug (eg, carboplatin) overlap each other. In some embodiments, the paclitaxel nanoparticle composition is administered for at least one cycle (eg, at least one of 2, 3, or 4 cycles) prior to administering the platinum-based agent. In some embodiments, a platinum-based agent (eg, carboplatin) is administered for any of at least 1, 2, 3, or 4 weeks. In some embodiments, the administration of the paclitaxel nanoparticle composition and the platinum-based agent (eg, carboplatin) is substantially simultaneously (eg, within 1 day, within 2 days, within 3 days, within 4 days, 5 days, Start within a day, within 6 days, or within 7 days). In some embodiments, the administration of the paclitaxel nanoparticle composition and the platinum-based agent (eg, carboplatin) is substantially simultaneously (eg, within 1 day, within 2 days, within 3 days, within 4 days, 5 days, End either within a day, within 6 days, or within 7 days). In some embodiments, administration of a platinum-based agent (eg, carboplatin) is performed after administration of the paclitaxel nanoparticle composition (eg, about 1, 2, 3, 4, 5, 6, 7, Continue for any of 8, 9, 10, 11, or 12 months). In some embodiments, administration of a platinum-based agent (eg, carboplatin) is initiated after initiation of administration of a paclitaxel nanoparticle composition (eg, about 1, 2, 3, 4, 5, 6, 7, 8 , After 9, 10, 11, or 12 months). In some embodiments, the administration of the paclitaxel nanoparticle composition and the administration of the platinum-based agent (eg, carboplatin) begin and end at approximately the same time. In some embodiments, the administration of the paclitaxel nanoparticle composition and the administration of the platinum-based agent (eg, carboplatin) are initiated at about the same time, and the administration of the platinum-based agent (eg, carboplatin) After completing administration of the particle composition, continue (eg, for any of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the administration of the paclitaxel nanoparticle composition and the administration of the platinum-based agent (eg, carboplatin) are stopped substantially simultaneously, and the administration of the platinum-based agent (eg, carboplatin) Begin after administration of the particulate composition (eg, after any of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) .

  In some embodiments, the administration of the paclitaxel nanoparticle composition and the administration of the platinum-based agent (eg, carboplatin) are non-concurrent. For example, in some embodiments, administration of the paclitaxel nanoparticle composition is terminated before administering a platinum-based agent (eg, carboplatin). In some embodiments, administration of the platinum-based agent (eg, carboplatin) is terminated prior to administering the paclitaxel nanoparticle composition. The period between these two non-synchronous administrations can range from about 2 to 8 weeks, such as about 4 weeks.

  The frequency of administration of the platinum-based drug (eg, carboplatin) may or may not be the same as the frequency of administration of the paclitaxel nanoparticle composition. The frequency of administration of nanoparticle compositions containing paclitaxel and platinum-based agents (eg, carboplatin) can be adjusted over the treatment period based on the judgment of the administering physician. When administered separately, the paclitaxel nanoparticle composition and the platinum-based agent (eg, carboplatin) can be administered at different dosing frequencies or at different dosing intervals. For example, a paclitaxel nanoparticle composition can be administered once a week, while a platinum-based agent (eg, carboplatin) can be administered more frequently or less frequently. In some embodiments, drug-containing nanoparticles and / or platinum-based drug sustained release formulations can be used. Various formulations and devices are known in the art for achieving sustained release. Combinations of the administration configurations described herein can also be used.

In some embodiments, the dose of paclitaxel in the nanoparticle composition is about 50 to about 125 mg / m 2 and the dose of a platinum-based drug (eg, carboplatin) is about AUC = 2 to about AUC = 6. . In some embodiments, the dose of paclitaxel in the nanoparticle composition is about 50 to about 125 mg / m 2 once a week and the dose of a platinum-based drug (eg, carboplatin) is about once every 3 weeks. AUC = 2 to about AUC = 6. In some embodiments, the dose of paclitaxel in the nanoparticle composition is about 100 mg / m 2 once a week and the dose of a platinum-based drug (eg, carboplatin) is about AUC = 6 once every 3 weeks. It is. In some embodiments, the dose of paclitaxel in the nanoparticle composition is about 75 mg / m 2 once a week and the dose of a platinum-based drug (eg, carboplatin) is about AUC = 4 once every 3 weeks. .5. In some embodiments, the dose of paclitaxel in the nanoparticle composition is about 50 mg / m 2 once a week and the dose of a platinum-based drug (eg, carboplatin) is about AUC = 3 once every 3 weeks. It is. In some embodiments, the paclitaxel nanoparticle composition and / or a platinum-based agent (eg, carboplatin) is administered intravenously. In some embodiments, the paclitaxel nanoparticle composition and a platinum-based agent (eg, carboplatin) are administered intravenously. In some embodiments, the platinum-based agent is carboplatin.

  The dose required for paclitaxel and / or platinum-based drugs (eg, carboplatin) may be lower (but not necessarily lower) than is normally required when each drug is administered alone. Also good). Thus, in some embodiments, a sub-therapeutic amount of drug is administered in the nanoparticle composition and / or platinum-based agent. “Subtherapeutic amount” or “subtherapeutic level” means sub-therapeutic amount, ie, when a drug and / or platinum-based agent (eg, carboplatin) in a nanoparticle composition is administered alone. Refers to an amount less than the amount normally used for. The reduction can be reflected in the amount administered at a given dose and / or can be reflected in the amount administered over a given period (reduced frequency).

  In some embodiments, the normal dose of drug in the nanoparticle composition required to perform the same treatment is at least about 5%, 10%, 20%, 30%, 50%, 60% Sufficient platinum-based agent (eg, carboplatin) to be allowed to be reduced in any of 70%, 80%, 90% or more. In some embodiments, a typical dose of a platinum-based agent (eg, carboplatin) required to perform a comparable treatment is at least about 5%, 10%, 20%, 30%, 50% Sufficient paclitaxel in the nanoparticle composition to allow a reduction in any of the following: 60%, 70%, 80%, 90% or more.

  In some embodiments, the dose of both paclitaxel and the platinum-based drug in the nanoparticle composition is reduced compared to each corresponding normal dose when administered alone. In some embodiments, both paclitaxel in the nanoparticle composition and the platinum-based agent are administered at a sub-therapeutic level, ie, a low level. In some embodiments, the dosage of the nanoparticle composition and / or platinum-based agent is substantially lower than the established maximum tolerated dose (MTD). For example, the dosage of the nanoparticle composition and / or platinum-based agent is less than about 50%, 40%, 30%, 20%, or 10% of the MTD.

  In some embodiments of any of the methods, the method further comprises administration of an effective amount of an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is bevacizumab, sunitinib, or sorafenib tosylate. In some embodiments, the anti-angiogenic agent is bevacizumab. In some embodiments, the effective amount of bevacizumab is about 5 mg / kg to about 15 mg / kg. In some embodiments, the effective amount of bevacizumab is either about 5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 15 mg / kg.

  Combinations of administration configurations described herein can be used. The combination therapy described herein can also be performed alone, and includes chemotherapy, radiation therapy, surgery, hormone therapy, gene therapy, immunotherapy, chemoimmunotherapy, hepatic artery based therapy, cryotherapy, ultra It can also be performed in combination with other therapies such as sonic therapy, local ablation therapy, radiofrequency ablation therapy, and photodynamic therapy. In addition, patients at high risk of developing NSCLC can be treated to inhibit and / or delay the onset of NSCLC.

In some embodiments, administration of the paclitaxel nanoparticle composition and the platinum-based agent (eg, carboplatin) is synchronic with radiation therapy (eg, chest radiation). In some embodiments, the administration of the paclitaxel nanoparticle composition is done contemporaneously with radiation therapy (eg, chest radiation). Radiation contemplated herein includes, for example, delivery of gamma rays, x-rays (external beams), and tumor cell directed radioisotopes. Other forms of DNA damaging factors are also contemplated, such as microwave and UV irradiation. Radiation can be delivered in a single dose or a series of small doses according to a dose split schedule. Radiation doses contemplated herein range from about 1 to about 100 Gy, including, for example, about 5 to about 80, about 10 to about 50 Gy, or about 10 Gy. The total dose can also be applied in a divided regime. For example, the regime may include 2 Gy individual fractional doses. The radioisotope dose range varies widely and depends on the half-life of the isotope and the intensity and type of radiation emitted. In some embodiments, the radiation can be performed in 25-40 divisions (eg, about 33 divisions) via 3D conformal methods or intensity modulation methods. In some embodiments, the dose of paclitaxel nanoparticle composition is about 20 mg / m 2 to about 60 mg / m 2 (eg, 40 mg / m 2 ) once a week and a platinum-based drug (eg, carboplatin) Dose of about AUC = 2 to AUC = 6 once a week (eg, AUC = 2), and the synchronic dose of chest radiation is about 25 via 3D conformal or intensity modulation methods. About 40 divisions (for example, about 33 divisions).

If the radiation involves the use of a radioisotope, the isotope can be conjugated to a targeting agent that carries the radionuclide to the target tissue, such as a therapeutic antibody. Suitable radioisotopes include astatine 211 , 14 carbon, 51 chromium, 36 chlorine, 57 iron, 58 cobalt, copper 67 , 152 Eu, gallium 67 , 3 hydrogen, iodine 123 , iodine 131 , indium 111 , 59 iron, 32 phosphorus, rhenium 186 , 75 selenium, 35 sulfur, technesium 99m , and / or yttrium 90, but are not limited to these.

Nanoparticle Compositions The nanoparticle compositions described herein comprise nanoparticles comprising (in various embodiments, consisting essentially of) paclitaxel (or docetaxel) and albumin (such as human serum albumin). . Nanoparticles of drugs with low water solubility (such as paclitaxel) are, for example, US Pat. Nos. 5,916,596; 6,506,405; each of which is incorporated in their entirety by reference. 6,749,868; 6,537,579; and 7,820,788, and US Patent Application Publication Nos. 2006/0263434 and 2007/0082838; PCT Patents It is also disclosed in application WO 08/137148. The following description focuses on nanoparticle compositions comprising paclitaxel, but this explanation also applies to nanoparticles comprising docetaxel.

  In some embodiments, the composition has an average or mean diameter of about 1000 nanometers, such as no more than about 900, 800, 700, 600, 500, 400, 300, 200, and 100 nm. Includes nanoparticles that are less than a meter (nm). In some embodiments, the nanoparticles have an average or mean diameter of about 200 nm or less. In some embodiments, the nanoparticles have an average or mean diameter of about 150 nm or less. In some embodiments, the nanoparticles have an average or mean diameter of about 100 nm or less. In some embodiments, the nanoparticles have an average or mean diameter of about 20 to about 400 nm. In some embodiments, the nanoparticles have an average or mean diameter of about 40 to about 200 nm. In some embodiments, the nanoparticles are sterile filterable.

  In some embodiments, the average diameter of the nanoparticles in the compositions described herein can be, for example, about 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80. , 70, or 60 nm, including about 200 nm or less. In some embodiments, at least about 50% of the nanoparticles in the composition (eg, any one of at least about 60%, 70%, 80%, 90%, 95%, or 99%) Is about 200 nm or less, including, for example, about 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 nm or less. is there. In some embodiments, at least about 50% of the nanoparticles in the composition (eg, any one of at least 60%, 70%, 80%, 90%, 95%, or 99%) About 20 to about 200 nm, about 40 to about 200 nm, about 30 to about 180 nm, and about 40 to about 150 nm, about 50 to about 120 nm, and about 60 to about 100 nm, including any one of about 20 It falls within the range of ˜about 400 nm.

  In some embodiments, the albumin has a sulfhydral group that can form a disulfide bond. In some embodiments, at least about 5% (eg, at least about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%) of albumin in the nanoparticle portion of the composition , 70%, 80%, or 90%) is cross-linked (eg, cross-linked via one or more disulfide bonds).

  In some embodiments, the nanoparticles comprise paclitaxel coated with albumin (eg, human serum albumin). In some embodiments, the composition comprises paclitaxel in both nanoparticulate and non-nanoparticulate forms, and at least about 50%, 60%, 70%, 80%, 90% of the paclitaxel in the composition. , 95%, or 99% is in nanoparticle form. In some embodiments, the paclitaxel in the nanoparticles is greater than about 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the nanoparticles. Occupy one of the following. In some embodiments, the nanoparticles have a non-polymeric matrix. In some embodiments, the nanoparticles comprise a core of paclitaxel that is substantially free of polymeric material (such as a polymer matrix).

  In some embodiments, the composition comprises albumin in both the nanoparticle portion and the non-nanoparticle portion, and at least about 50%, 60%, 70%, 80%, 90% of the albumin in the composition. %, 95%, or 99% is in the non-nanoparticle portion of the composition.

  In some embodiments, the weight ratio of albumin (such as human serum albumin) to paclitaxel in the nanoparticle composition is about 15: 1 or less, such as about 18: 1 or less, such as about 10: 1 or less. In some embodiments, the weight ratio of albumin (such as human serum albumin) to paclitaxel in the composition is about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1. It falls within the range of any one of about 13: 1, about 4: 1 to about 12: 1, or about 5: 1 to about 10: 1. In some embodiments, the weight ratio of albumin to paclitaxel in the nanoparticle portion of the composition is about 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15 or less. In some embodiments, the weight ratio of albumin (such as human serum albumin) to paclitaxel in the composition is: about 1: 1 to about 18: 1, about 1: 1 to about 15: 1, about 1: 1 to about 12: 1, about 1: 1 to about 10: 1, about 1: 1 to about 9: 1, about 1: 1 to about 8: 1, about 1: 1 to about 7: 1, about 1: 1 to about 6: 1, about 1: 1 to about 5: 1, about 1: 1 to about 4: 1, about 1: 1 to about 3: 1, about 1: 1 to about 2: 1, or about 1 : Any one of 1 to about 1: 1.

  In some embodiments, the nanoparticle composition includes one or more of the above features.

  The nanoparticles described herein may be present in a dry formulation (such as a lyophilized composition) or suspended in a biocompatible medium. Suitable biocompatible media include water, aqueous buffer media, saline, buffered saline, optionally amino acid buffer, optionally protein buffer, optionally sugar buffer, optionally , Including but not limited to, buffer solutions of vitamins, and optionally, buffer solutions of synthetic polymers, lipid-containing emulsions and the like.

In some embodiments, the pharmaceutically acceptable carrier comprises human serum albumin. The human serum albumin (HSA), a highly soluble globular protein of M r 65K, made of 585 amino acids. HSA is the most abundant protein in plasma and accounts for 70-80% of the colloid osmotic pressure of human plasma. The amino acid sequence of HSA contains a total of 17 disulfide bridges, one free thiol (Cys34), and a single tryptophan (Trp214). Intravenous use of HSA solutions has been shown for the prevention and treatment of hypobolic shock (eg, Tullis, JAMA, 237, 355-360, 460-463 (1977), and (See, eg, Finlayson, Seminars in Thrombosis). and Hemostasis, 6, 85-120 (1980)). Other albumins are also contemplated, such as bovine serum albumin. Such use of non-human albumin may be appropriate in the context of the use of these compositions in non-human mammals, such as, for example, vertebrates (vertebrates, including domestic pets and agriculture). Let's go.

  Human serum albumin (HSA) has multiple hydrophobic binding sites (a total of 8 binding sites for fatty acids that are endogenous ligands of HSA), and a diverse set of taxanes, especially neutral hydrophobic compounds And binds to negatively charged hydrophobic compounds (Goodman et al., “The Pharmaceutical Basis of Therapeutics”, 9th edition, McGraw-Hill New York (1996)). In the HSA IIA and IIIA subdomains, two high-affinity binding sites have been proposed, with charged lysine and charged arginine residues near the surface that serve as binding points for polar ligand features. A very elongated hydrophobic pocket (eg Fehske et al., Biochem. Pharmcol., 30, 687-92 (198a), Volum, Dan. Med. Bull., 46, 379-99 (1999)). Kragh-Hansen, Dan. Med. Bull., 1441, 131-40 (1990), Curry et al., Nat. Struct. Biol., 5, 827-35 (1998), Sugio et al., Protein. Eng., 12 439-46 (1999), He et al., Nature, 358, 209-15 (199b), and Carter et al., Adv. Protein. Chem., 45, 153-203 (1994). I want to be) Paclitaxel has been shown to bind to HSA (see, eg, Paal et al., Eur. J. Biochem., 268 (7), 2187-91 (200a)).

  Albumin (such as human serum albumin) in the composition generally functions as a carrier for paclitaxel. That is, the albumin in the composition makes paclitaxel more easily suspendable in an aqueous medium or helps maintain this suspension as compared to a composition without albumin. This can avoid the use of toxic solvents (or surfactants) to solubilize paclitaxel, thereby causing one or more side effects from administering paclitaxel to an individual (such as a human). Can be reduced. Accordingly, in some embodiments, the compositions described herein are substantially free of surfactant (such as Cremophor (including Cremophor EL® (BASF))). Etc.) In some embodiments, the nanoparticle composition is substantially free of surfactant (eg, free of surfactant). When a nanoparticulate composition is administered to an individual, if the amount of Cremophor or surfactant in the composition is not sufficient to cause one or more side effects in the individual, the composition is said to be “substantially Cremophor. Or “substantially free of surfactant”. In some embodiments, the nanoparticle composition comprises less than about any one of about 20%, 15%, 10%, 7.5%, 5%, 2.5%, or 1% organic solvent. Or a surfactant is contained.

  The amount of albumin in the composition described herein will vary depending on the other components in the composition. In some embodiments, the composition is in an amount sufficient to stabilize paclitaxel in the form of an aqueous suspension, eg, a stable colloidal suspension (such as a stable nanoparticle suspension). Contains albumin. In some embodiments, albumin is an amount that reduces the sedimentation rate of paclitaxel in an aqueous medium. For particle-containing compositions, the amount of albumin also depends on the size and density of the paclitaxel nanoparticles.

  Paclitaxel is at least about 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48 When maintained in suspension in an aqueous medium for an extended period of time, such as over one of 60, 72, or 72 hours (such as suspension without visible precipitation or sedimentation), paclitaxel is “Stabilized”. Suspensions are generally suitable for administration to an individual (such as a human), but are not necessarily suitable for administration to an individual. Suspension stability is generally assessed at storage temperature (such as room temperature (such as 20-25 ° C.) or refrigerated conditions (such as 4 ° C.)) (but not necessarily at storage temperature). For example, approximately 15 minutes after preparation of the suspension, the flocculation or particles that are visible to the naked eye, or visible when viewed under a 1000X optical microscope. If there is no aggregation, the suspension is stable at storage temperature. Stability can also be evaluated under accelerated test conditions, such as temperatures above about 40 ° C.

  In some embodiments, albumin is present in an amount sufficient to stabilize paclitaxel in a particular concentration of aqueous suspension. For example, the paclitaxel concentration in the composition can be, for example, about 0.1 to about 50 mg / ml, about 0.1 to about 20 mg / ml, about 1 to about 10 mg / ml, about 2 mg / ml to about 8 mg / ml, About 0.1 to about 100 mg / ml, including any of about 4 to about 6 mg / ml and about 5 mg / ml. In some embodiments, the concentration of paclitaxel is at least about 1.3 mg / ml, 1.5 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, One of 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 40 mg / ml, and 50 mg / ml. In some embodiments, albumin is present in an amount that avoids the use of a surfactant (such as Cremophor) so that the composition is free or substantially free of a surfactant (such as Cremophor). To do.

  In some embodiments, the composition in liquid form has about 0.1% to about 50% (w / v) (eg, about 0.5% (w / v), about 5% (w / v) ), About 10% (w / v), about 15% (w / v), about 20% (w / v), about 30% (w / v), about 40% (w / v), or about 50 % (W / v)) albumin. In some embodiments, the composition in liquid form comprises about 0.5% to about 5% (w / v) albumin.

  In some embodiments, the weight ratio of albumin (eg, albumin) to paclitaxel in the nanoparticle composition is such that a sufficient amount of paclitaxel binds to or is transported by the cell. Depending on the different combinations of albumin and paclitaxel, the weight ratio of albumin to paclitaxel must be optimized, but generally the weight ratio of albumin (eg, albumin) to paclitaxel (w / w) is about 0.01: 1 to about 100: 1, about 0.02: 1 to about 50: 1, about 0.05: 1 to about 20: 1, about 0.1: 1 to about 20: 1, about 1: 1 to about 18 1: about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, about 5: 1 to about 9: 1, or about 9: 1. . In some embodiments, the weight ratio of albumin to paclitaxel is about 18: 1 or less, 15: 1 or less, 14: 1 or less, 13: 1 or less, 12: 1 or less, 11: 1 or less, 10: 1 or less. 9: 1 or less, 8: 1 or less, 7: 1 or less, 6: 1 or less, 5: 1 or less, 4: 1 or less, and 3: 1 or less. In some embodiments, the weight ratio of albumin (such as human serum albumin) to paclitaxel in the composition is: about 1: 1 to about 18: 1, about 1: 1 to about 15: 1, about 1: 1 to about 12: 1, about 1: 1 to about 10: 1, about 1: 1 to about 9: 1, about 1: 1 to about 8: 1, about 1: 1 to about 7: 1, about 1: 1 to about 6: 1, about 1: 1 to about 5: 1, about 1: 1 to about 4: 1, about 1: 1 to about 3: 1, about 1: 1 to about 2: 1, or about 1 : Any one of 1 to about 1: 1.

  In some embodiments, albumin allows the composition to be administered to an individual (such as a human) without significant side effects. In some embodiments, albumin (such as human serum albumin) is an amount effective to reduce one or more side effects of administering paclitaxel to a human. The term “reduction of one or more side effects when administering paclitaxel” refers to one or more undesirable effects caused by paclitaxel, as well as the delivery vehicle used to deliver paclitaxel (paclitaxel suitable for injection). Refers to the reduction, mitigation, removal, or avoidance of side effects caused by the intended solvent. In some embodiments, the one or more side effects are adverse side effects (AE). In some embodiments, the one or more side effects are severe adverse side effects (SAE). Such side effects include, for example, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever, anaphylactic reaction, venous thrombosis, Extravasation, and combinations thereof are included. However, these side effects are only exemplary and other side effects or combinations of side effects associated with paclitaxel can be reduced.

  In some embodiments, the nanoparticle composition comprises Abraxane® (Nab-paclitaxel). In some embodiments, the nanoparticle composition is Abraxane® (Nab-paclitaxel). Abraxane® is a paclitaxel formulation stabilized by human albumin USP and can be dispersed in a physiological solution that is directly injectable. When dispersed in a suitable aqueous medium, such as 0.9% sodium chloride injection or 5% dextrose injection, Abraxane® forms a stable colloidal suspension of paclitaxel. The average particle size of the nanoparticles in the colloidal suspension is about 130 nanometers. HSA has a high solubility in water (freely soluble), eg, from about 2 mg / ml to about 8 mg / ml, including about 5 mg / ml, concentrated from dilution (0.1 mg / ml paclitaxel) (20 mg / ml Abraxane <(R)> can be reconstituted at a wide range of concentrations over a range of.

  Methods for making nanoparticle compositions are known in the art. For example, nanoparticles containing paclitaxel and albumin (such as human serum albumin) can be prepared under high shear force conditions (eg, sonication, high pressure homogenization, etc.). These methods are described, for example, in US Pat. Nos. 5,916,596; 6,506,405; 6,749,868; 6,537,579; and 7,820. 788, US Patent Application Publication Nos. 2007/0082838, 2006/0263434, and PCT Application No. WO08 / 137148.

  Briefly, paclitaxel can be dissolved in an organic solvent and this solution added to the albumin solution. This mixture is subjected to high pressure homogenization. The organic solvent can then be removed by evaporation. The resulting dispersion can be further lyophilized. Suitable organic solvents include, for example, ketones, esters, ethers, chlorinated solvents, and other solvents known in the art. For example, the organic solvent can be methylene chloride or chloroform / ethanol (eg, 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4, 1: 3, 1: 2, 1: 1). 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1 ratio).

Other Components in Nanoparticle Composition The nanoparticles described herein can be present in a composition that includes other agents, excipients, or stabilizers. For example, certain negatively charged components can be added to increase stability by increasing the negative zeta potential of the nanoparticles. Such negatively charged components include glycocholate, cholic acid, chenodeoxycholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dehydrocholic acid, etc. Acids, the following phosphatidylcholine: lecithin (lipid yolk) containing palmitoyl oleoylphosphatidylcholine, palmitoyllinoleoylphosphatidylcholine, stearoyllinoleoylphosphatidylcholine, stearoyloleoylphosphatidylcholine, stearoylarachidoylphosphatidylcholine, and dipalmitoylphosphatidylcholine Including but not limited to phospholipids. Other phospholipids include L-α-dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), distearoylphosphatidylcholine (DSPC), hydrogenated soybean phosphatidylcholine (HSPC), and other related compounds. Can be mentioned. Negatively charged surfactants or emulsifiers such as sodium cholesteryl sulfate are also suitable as additives.

  In some embodiments, the composition is suitable for human administration. In some embodiments, the composition is suitable for administration to mammals such as domestic pets and agricultural animals in a veterinary context. There are suitable formulations of a wide variety of nanoparticle compositions (see, eg, US Pat. Nos. 5,916,596 and 6,096,331). The following formulations and methods are merely exemplary and are in no way limiting. Formulations suitable for oral administration include (a) a liquid solution such as an effective amount of a compound dissolved in a diluent such as water, saline, or orange juice, (b) each of which is a solid or granule It may consist of capsules, sachets, or tablets containing a certain amount of active ingredient, (c) a suspension in a suitable liquid, and (d) a suitable emulsion. Tablet forms include lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia gum, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients , Colorants, diluents, buffers, humectants, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms may contain savory active ingredients, usually sucrose and acacia gum or tragacanth gum, and lozenges containing active ingredients in an inert base such as gelatin and glycerin, or sucrose and acacia gum, active ingredients In addition, emulsions, gels, and the like containing excipients known in the art can be included.

  Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginic acid, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, Cellulose, water, saline solution, syrup, methylcellulose, methylhydroxybenzoic acid and propylhydroxybenzoic acid, talc, magnesium stearate, and mineral oil include, but are not limited to. The formulations can further include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.

  Formulations suitable for parenteral administration include aqueous and non-aqueous, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation compatible with the blood of the intended recipient. Tonic sterile sterile solutions are included, as well as aqueous and non-aqueous sterile suspensions that may include suspending, solubilizing, thickening, stabilizing, and preserving agents. The formulation can be present in unit-dose or multiple-dose sealed containers such as ampoules and vials, and just before the use is added a sterile liquid excipient for injection, such as water. Can be stored under freeze-dried (lyophilized) conditions. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, sterile granules, and sterile tablets of the kind previously described. Injectable formulations are preferred.

  In some embodiments, including, for example, any pH range from about 5.0 to about 8.0, from about 6.5 to about 7.5, and from about 6.5 to about 7.0, The composition is formulated to have a pH range of about 4.5 to about 9.0. In some embodiments, the composition is formulated to have a pH of about 6 or more, including, for example, any of about 6.5, 7, or 8 (such as about 8) or more. The composition can also be made isotonic with blood by the addition of a suitable tonicity modifier such as glycerol.

Kits, medicaments, and compositions The present invention also provides kits, medicaments, compositions, and unit dosage forms for use in any of the methods described herein.

  The kit of the invention comprises one or more containers comprising a nanoparticle composition (or unit dosage form and / or manufactured product) containing paclitaxel and / or a platinum-based agent, and in some embodiments, Further included are instructions for use in accordance with any of the methods described herein. The kit can further include instructions for selecting individuals suitable for treatment. The instructions provided in the kit of the present invention are typically instructions written on a label or package insert (eg, a paper sheet included in the kit), but are machine readable. Possible instructions (eg, instructions written on a magnetic storage disk or an optical storage disk) are also acceptable.

  For example, in some embodiments, the kit treats a) a composition comprising nanoparticles comprising paclitaxel and albumin (such as human serum albumin), b) an effective amount of a platinum-based agent, and c) NSCLC. Instructions for administering the nanoparticle composition and the platinum-based agent. The nanoparticles and the platinum-based drug can be present in separate containers or can be present in a single container. For example, a kit may contain one unique composition, two or more compositions, one composition containing nanoparticles, and the other composition containing a platinum-based drug. is there.

  The kit of the present invention is suitably packaged. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, Mylar or plastic bags), and the like. The kit may optionally provide additional components such as buffering and interpretation information. Thus, the application also provides manufactured products that include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.

Instructions regarding the use of paclitaxel nanoparticle compositions and platinum-based agents (eg, carboplatin) generally include information about the intended dose, dosing schedule, and route of administration. In some embodiments, the instructions include a paclitaxel nanoparticle composition with a dosage of about 50 to about 125 mg / m 2 and a platinum-based drug with a dosage of about AUC = 2 to about AUC = 6 (eg, Carboplatin) should be administered. In some embodiments, the instructions are administered for the intended treatment from about 50 to about 125 mg / m 2 as a dose of a paclitaxel nanoparticle composition administered once a week, and once every three weeks. Indicates that about AUC = 2 to about AUC = 6 should be used as the dose of a platinum-based drug (eg, carboplatin). In some embodiments, the instructions include a platinum-based dose of about 100 mg / m 2 as the dose of paclitaxel nanoparticle composition administered once a week for the intended treatment, and once every three weeks. Indicates that about AUC = 6 should be used as the dose of other drugs (eg, carboplatin). In some embodiments, the instructions are about 75 mg / m 2 as a dose of paclitaxel nanoparticle composition administered once a week for the intended treatment, and platinum-based administered once every three weeks. Indicates that AUC = 4.5 should be used as the dose of other drugs (eg carboplatin). In some embodiments, the instructions include, for the intended treatment, about 50 mg / m 2 as a dose of paclitaxel nanoparticle composition once a week, and a platinum-based drug administered once every three weeks ( For example, it shows that about AUC = 3 should be used as the dose of carboplatin. In some embodiments, the instructions administer the paclitaxel nanoparticle composition at a dose of about 20 mg / m 2 to about 60 mg / m 2 (eg, about 40 mg / m 2 ) once a week, A platinum-based drug (eg, carboplatin) at about AUC = 2 to AUC = 6 (eg, AUC = 2) is administered once a week, and the dose is 3D conformally or intensity modulated at the same time It shows that chest radiation irradiation is performed in about 25 to about 40 divisions (for example, about 33 divisions) through the law. In some embodiments, the instructions indicate intravenous administration of the paclitaxel nanoparticle composition and / or a platinum-based agent (eg, carboplatin). In some embodiments, the instructions indicate intravenous administration of the paclitaxel nanoparticle composition and a platinum-based agent (eg, carboplatin). In some embodiments, the instructions indicate that the platinum-based agent is carboplatin.

  In some embodiments, the kit comprises a paclitaxel nanoparticle composition and a platinum-based agent (i) a squamous cell carcinoma, (ii) a difference in the level of caveolin-1 (CAV1), (iii) SPARC. Level difference, (iv) level difference of hypoxia marker, (v) level difference of tumor acidity, (vi) level difference of gp60, (vii) level difference of thymidylate synthase (TS), (Viii) S-phase kinase-related protein (Skp2) level difference, (ix) single nucleotide polymorphism (SNP) loss of heterozygosity (LOH), (x) Kras mutation difference, (xi) tumor One or more features of NSCLC selected from the group consisting of: methylation differences in promoter regions of related genes, and (xii) differences in albumin uptake It is intended for treating an individual to be displayed that is shown (i.e., shown) to provide a label.

  The container may be a unit dose, a bulk package (eg, a multiple dose package), or a sub-unit dose. For example, 1 week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, A kit containing paclitaxel at a dose disclosed herein sufficient to provide effective treatment to an individual over a long period of time, such as any of 7 months, 8 months, 9 months or more Can be provided.

  The kit also includes multiple unit doses of paclitaxel and pharmaceutical composition and instructions for use, and is packaged in an amount sufficient to be stored and used in a pharmacy, such as a hospital pharmacy and a dispensing pharmacy. Is also possible.

  Also provided are medicaments, compositions, and unit dosage forms useful in the methods described herein. In some embodiments, a medicament (or composition or unit dosage form) used with a platinum-based agent to treat NSCLC, comprising nanoparticles comprising paclitaxel and albumin (such as human serum albumin) A medicament (or composition or unit dosage form) is provided. In some embodiments, a medicament (or composition or unit dosage form) used to treat NSCLC comprising nanoparticles comprising paclitaxel and albumin (such as human serum albumin) and a platinum-based agent. A medicament (or composition or unit dosage form) is provided.

Exemplary Embodiments 1. A method of treating non-small cell lung cancer (NSCLC) in an individual in need thereof comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum-based Administering the agent, wherein the NSCLC is squamous cell carcinoma.

  2. A method of treating NSCLC in an individual comprising the steps of: a) administering an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and b) an effective amount of a platinum-based agent, , (I) squamous cell carcinoma, (ii) differential levels of caveolin-1 (CAV1), (iii) differential levels of SPARC, (iv) differential levels of hypoxia markers, (v) tumor acidity Degree difference, (vi) difference in level of gp60, (vii) difference in level of thymidylate synthase (TS), (viii) difference in level of S phase kinase related protein (Skp2), (ix) single base Polymorphism (SNP) loss of heterozygosity (LOH), (x) Kras mutation, (xi) methylation of promoter region of tumor-related genes Different, and (xii) based on NSCLC having one or more features selected from the group consisting of the difference in albumin uptake method.

  3. NSCLC: (a) squamous cell carcinoma, (b) differential level of caveolin-1 (CAV1), (c) differential level of SPARC, (d) differential level of hypoxia marker, (e) Differences in tumor acidity levels, (f) differences in levels of gp60, (g) differences in levels of thymidylate synthase (TS), (h) differences in levels of S-phase kinase-related protein (Skp2), (i) Single nucleotide polymorphism (SNP) heterozygous loss (LOH) difference, (j) Kras mutation difference, (k) Tumor associated gene promoter region methylation difference, and (l) Albumin uptake difference A method of treating NSCLC in an individual when known to have one or more characteristics selected from the group consisting of i) paclitaxel and An effective amount of a composition comprising nanoparticles comprising a fine albumin, comprising administering a ii) an effective amount of a platinum-based agent, the method.

  4). (A) selecting individuals with NSCLC, wherein the NSCLC is (i) squamous cell carcinoma, (ii) caveolin-1 (CAV1) level difference, (iii) SPARC level difference, (Iv) differences in levels of hypoxia markers, (v) differences in levels of tumor acidity, (vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) S Phase kinase related protein (Skp2) level difference, (ix) single nucleotide polymorphism (SNP) heterozygosity loss (LOH) difference, (x) Kras mutation difference, (xi) tumor related gene promoter (B) having one or more characteristics selected from the group consisting of a region methylation difference and (xii) a difference in albumin uptake; How to selected individuals, i) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin, and including the step of administering a platinum-based agent ii) an effective amount, treating NSCLC as.

  5. A method for assessing whether treatment is effective for an individual with NSCLC, comprising: (a) squamous cell carcinoma; (b) a difference in caveolin-1 (CAV1) levels; (c) a level of SPARC Difference, (d) hypoxia marker level difference, (e) tumor acidity level difference, (f) gp60 level difference, (g) thymidylate synthase (TS) level difference, (h ) Differences in the level of S-phase kinase-related protein (Skp2), (i) loss of heterozygosity of single nucleotide polymorphism (SNP) (LOH), (j) difference in Kras mutation, (k) tumor-related gene Evaluating one or more characteristics of NSCLC selected from the group consisting of: (1) a difference in methylation of the promoter region of One or more indicates that the treatment is responsive to the individual, the treatment comprising i) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and ii) an effective amount of a platinum-based agent; Method.

  6). A method of identifying an individual with NSCLC that is likely to benefit from a treatment comprising a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent comprising: (A) (i ) Squamous cell carcinoma, (ii) differential level of caveolin-1 (CAV1), (iii) differential level of SPARC, (iv) differential level of hypoxia marker, (v) level of tumor acidity (Vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) differences in levels of S-phase kinase-related protein (Skp2), (ix) single nucleotide polymorphisms ( SNP) loss of heterozygosity (LOH), (x) differences in Kras mutation, (xi) differences in promoter region methylation of tumor-associated genes, and (x i) evaluating one or more characteristics of NSCLC selected from the group consisting of differences in albumin uptake; and (B) (i) squamous cell carcinoma, (ii) caveolin-1 (CAV1) Level difference, (iii) SPARC level difference, (iv) hypoxia marker level difference, (v) tumor acidity level difference, (vi) gp60 level difference, (vii) thymidylate Synthase (TS) level difference, (viii) S phase kinase related protein (Skp2) level difference, (ix) single nucleotide polymorphism (SNP) loss of heterozygosity (LOH), (x) NS selected from the group consisting of a difference in Kras mutations, (xi) a difference in the methylation of the promoter region of a tumor-associated gene, and (xii) a difference in albumin uptake And a step of identifying individuals who have one or more characteristics of LC, method.

  7). A method of marketing a combination therapy comprising a composition comprising nanoparticles comprising paclitaxel and albumin and b) a platinum-based agent for use in a subpopulation of NSCLC individuals comprising: (i) flattening Epithelial cell carcinoma, (ii) differential level of caveolin-1 (CAV1), (iii) differential level of SPARC, (iv) differential level of hypoxia marker, (v) differential level of tumor acidity (Vi) differences in levels of gp60, (vii) differences in levels of thymidylate synthase (TS), (viii) differences in levels of S-phase kinase-related protein (Skp2), (ix) single nucleotide polymorphisms (SNPs) Loss of heterozygosity (LOH), (x) differences in Kras mutation, (xi) differences in promoter region methylation of tumor-associated genes, and (x i) inform target customers about the use of combination therapy to treat a sub-population of individuals characterized by one or more NSCLC-characteristic sub-populations selected from the group consisting of differences in albumin uptake A method comprising steps.

  8). Embodiment 8. The any one of embodiments 2-7, wherein the difference in the level of hypoxia is a difference in the level of carbonic anhydrase 9 (CA-9) or a difference in the level of LDH (eg, LDH-5). the method of.

  9. Embodiments 2-7, wherein the difference in level of tumor acidity is a difference in level of HIF-1α, a difference in level of HIF-2α, or a level of differentiated embryonic chondrocyte expression gene 1 (DEC-1) The method as described in any one of these.

10. The method according to the effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin is about 50 mg / m 2 ~ about 125 mg / m 2, any one of embodiments 1-9.

11. The method of embodiment 10, wherein the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is about 50 mg / m 2 , about 75 mg / m 2 , or about 100 mg / m 2 .

  12 The method of any one of embodiments 1-11, wherein the composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week.

  13. The method of any one of embodiments 1-11, wherein the effective amount of the platinum-based agent is from about AUC = 2 to about AUC = 6.

  14 The method of embodiment 13, wherein the effective amount of the platinum-based agent is AUC = 3, AUC = 4.5, or AUC = 6.

  15. The method of any one of embodiments 1-14, wherein the platinum-based agent is administered once every 3 weeks.

16. A method of treating NSCLC in an individual in need thereof comprising administering to an individual (a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; and (b) an effective amount of a platinum-based agent. An effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 100 mg / m 2 (once weekly) and an effective amount of a platinum-based drug is AUC = 6 (every 3 weeks A single dose).

17. A method of treating NSCLC in an individual in need thereof comprising: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin; b) an effective amount of a platinum-based agent; and c) a breast. An effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin is 40 mg / m 2 or 60 mg / m 2 (once weekly) and an effective amount of a platinum-based drug Where AUC = 2 (once weekly) and synchronic, thorax radiation is divided into 33 via 3D conformal or intensity modulation methods.

  18. Embodiment 18. The method of any one of embodiments 1-17, wherein the paclitaxel in the nanoparticles is coated with albumin.

  19. Embodiment 19. The method of any one of embodiments 1 through 18, wherein the average diameter of the nanoparticles in the composition is about 200 nm or less.

  20. The method of embodiment 19, wherein the average diameter of the nanoparticles in the composition is less than about 200 nm.

  21. Embodiments in which the NSCLC is early NSCLC, non-metastatic NSCLC, primary NSCLC, advanced NSCLC, locally advanced NSCLC, metastatic NSCLC, remission NSCLC, recurrent NSCLC, NSCLC in adjuvant status, or NSCLC in neoadjuvant status The method according to any one of 1 to 20.

  22. Embodiments 1-21 wherein the NSCLC is a latent NSCLC, stage 0 NSCLC, stage I NSCLC, stage II NSCLC, stage IIIA NSCLC, stage IIIB NSCLC, or stage IV NSCLC The method as described in any one of these.

  23. 23. The method of embodiment 22, wherein the NSCLC is stage IIIB NSCLC or stage IV NSCLC.

  24. The method of any one of embodiments 1 to 23, wherein the method is a first line therapy.

  25. Embodiment 25. The method of any one of embodiments 1-24, wherein the composition comprising nanoparticles comprising paclitaxel and albumin, and the platinum-based agent are administered parenterally.

  26. 26. The method of embodiment 25, wherein the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based agent are administered intravenously.

  27. Embodiment 27. The method of any one of embodiments 1-26, wherein the composition comprising nanoparticles comprising paclitaxel and albumin is administered without any steroid pre-medication and / or without G-CSF prophylaxis. .

  28. Embodiment 28. The method of any one of embodiments 1-27, wherein the composition comprising nanoparticles comprising paclitaxel and albumin is administered over 30 minutes.

  29. The method according to any one of embodiments 1-28, wherein the platinum-based agent is carboplatin.

  30. 30. The method of any one of embodiments 1-29, wherein the individual is a human.

  Those skilled in the art will recognize that multiple embodiments are possible within the scope and spirit of the invention. The invention will now be described in more detail by reference to the following non-limiting examples. The following examples further illustrate the invention but, of course, should not be considered as limiting its scope in any way.

Example 1
Randomized phase III clinical trial of Nab-paclitaxel and carboplatin® (Taxol® and carboplatin (registration) as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) Trademark))
Clinical studies show that Nab-paclitaxel + carboplatin (AUC = 6) vs. Taxol® and carboplatin (AUC = 6) disease response as first-line therapy in patients with advanced NSCLC (using RECIST guidelines Compared). In addition, clinical studies have shown that CTCAE; progression-free survival (PFS); patient survival; duration of response in responding patients; assessment of pharmacokinetic parameters; and acid and cysteine-rich in tumor tissue and peripheral blood Evaluation of secreted protein (SPARC) and other molecular biomarkers was used to compare the frequency of toxicity grades and determine their potential correlation with efficacy results.

Treatment Design This is the safety of intravenous Nab-paclitaxel / carboplatin combination therapy as a first line therapy in patients with NSCLC compared to the safety / tolerability and anti-tumor effect of Taxol / carboplatin combination therapy It was a multicenter phase III trial designed, managed and randomized to assess tolerability and anti-tumor effects. Patients were randomized to one of two treatment arms.

  Baseline assessments were performed on all patients to determine eligibility for the study. These assessments were completed within 28 days of randomization.

  A clinical assessment was performed at baseline, including: a) medical history (including specific information about any previous therapy and cardiac abnormalities); b) serum β-hCG pregnancy test (only women with a potential pregnancy) And eligibility of patients was determined within 72 hours of the first dose of study drug; c) 12-lead ECG; d) collection of blood samples for evaluation of molecular biomarkers; e) breast, liver and CT scan of the abdomen as well as any other studies required for tumor imaging; f) Nuclear medical bone scan at baseline for any patient with clinical symptoms that may have metastasized to bone G) CT scan of the head or MRI of the brain (if symptoms of metastasis to the brain are present); h) Calculation of height, weight and BSA; i) Physical examination and ECOG (Zubrod) machine Performance status scale; j) concomitant drug assessment (only drugs taken within 30 days prior to baseline visit); k) peripheral neuropathy assessment (doctor and patient assessment); l) Vital signs; m) CBC, white blood count and platelet count; and n) clinical chemistry panel (contains minimally serum transaminase, bilirubin, alkaline phosphatase, glucose, BUN and creatinine). The same mode of imaging was used at baseline and throughout the study. The creation of CT images followed the specifications provided in the RECIST guidelines.

  Treatment Phase Assessment—Patients were revisited within 7 days of randomization and cycle 1 of study drug administration was initiated. Visits (no response assessment was performed) were within ± 2 days of the planned visit date. Response assessments were performed every 6 weeks at any time during the 6th week. If the dose was skipped due to toxicity during the cycle, the dose was not compensated and the dose was recorded as the skipped dose.

  Evaluations including the following were performed before dosing or on the first day of each cycle: a) Physical examination (within 1 week of each cycle or within 1 week before the first day of each cycle) and ECOG functional status scale; b) Collection of blood samples for molecular biomarker evaluation (cycles 1, 5, 7, etc., day 1); c) body weight; d) concomitant drug evaluation; e) evaluation of peripheral neuropathy (1 day of each cycle) Within 1 week prior to eye or day 1 of each cycle); f) vital signs; g) assessment of adverse events (each dose); h) CBC, leukocyte classification and platelet count, and i) clinical chemistry panel (serum transaminase) , Bilirubin, alkaline phosphatase, glucose, BUN and creatinine to a minimum).

  Assessments including the following were performed weekly (days 8 and 15) during each cycle: a) concomitant drug assessment; b) adverse event assessment; and c) CBC, leukocyte classification and platelet count. CT scans of the breast, liver and abdomen and any other studies required for tumor imaging were performed every 6 weeks during treatment.

  End-of-study assessment—End-of-study assessment was performed when treatment was completed for any reason. Laboratory and clinical evaluations were performed to assess adverse events when treatment was completed. Patients who did not develop progressive disease before stopping treatment received tumor imaging studies performed every 6 weeks until tumor progression was confirmed.

  End-of-treatment assessment included: a) Physical examination and ECOG functional status scale; b) CT scans of breast, liver and abdomen and any other studies required for tumor imaging (specified studies) C) body weight; d) evaluation of concomitant medications; e) evaluation of peripheral neuropathy; f) vital signs; g) adverse event evaluation; h) CBC, leukocyte classification and platelets Number; and i) Clinical chemistry panel (contains minimally serum transaminase, bilirubin, alkaline phosphatase, glucose, BUN, creatinine).

  Assessment of follow-up of adverse events (AEs)-any AE or serious adverse event that occurred from the first dose of study drug to 30 days after the last study drug or during EOS (whichever is later) Events (SAE) were collected. Follow-up of AEs was performed as follows: a) Non-serious AEs other than neuropathy were followed for 30 days after the patient's final dose of study drug; b) Neuropathy was grade 1 improvement Followed until it occurred, at least 3 months without improvement or worsening, or until the patient started any other anti-cancer therapy during follow-up; and c) All SAEs ( Followed to resolution (regardless of relationship to study drug).

  Follow-up assessments include studies necessary for resolution of AEs or confirmation of any remaining unresolved AEs, eg, a) physical examination and ECOG functional status scale; b) chest, liver and abdominal CT scans and Any other studies required for tumor imaging; c) body weight; d) concomitant drug assessment; e) assessment of peripheral neuropathy; f) vital signs; g) assessment of AE events; and h) CBC, leukocytes Classification and platelet count; and clinical chemistry panel were included.

  Follow-up of patient survival after study-Patient status is assessed once a month for 6 months and then every 3 months for the next 12 months (18 months follow-up) after the study by phone To obtain survival data after the study.

  Withdrawal-Patient withdrew from the study if any of the following occurred: a) progressive disease; b) occurrence of unacceptable toxicity in the investigator's view; c) patient refuses to continue therapy D) if there is a recurrence of grade 4 neutropenia, any other grade 3 or 4 hematotoxicity, or any grade 3 or 4 non-myelosuppressive AE after the second dose reduction ( Except at the investigator's discretion, where there is evidence of benefit to the patient over and beyond the risk of recurrent toxicity); d) initiation of other anti-cancer therapies; or e) investigator's judgment In this case, discontinuing the study is the best benefit for the patient.

  A summary of the protocol for this study is provided in Table 1.

A EOS = end of study. When the patient finished the study, the indicated test was conducted. Repeat tumor response studies only as required by the prescribed study imaging schedule.

  B AE / SAE reporting continued for 30 days after the patient stopped study drug or EOS, whichever was later. Any AE / SAE that began during this time was also followed. If there was no AE or SAE continuation at the EOS visit, follow-up was performed by phone call to the patient once a week for up to 30 days from the last dose of treatment.

  C Pregnancy tests were required only for women with a potential pregnancy. A serum β-hCG pregnancy test was performed to assess patient eligibility within 72 hours of the first dose of study drug.

  DECG was performed at baseline and at any other stage of the cycle determined to be clinically significant by the investigator.

  Samples for E molecular biomarkers were obtained within 2 weeks prior to the first dose of study drug (included on day 1 of cycle 1, prior to study chemotherapy administration). All subsequent samples were taken on the first day of odd numbered cycles (cycles 3, 5, 7, etc.) prior to study drug administration.

  F All patients had measurable tumor (s) shown on radiographs according to RECIST criteria: CT scans of chest, abdomen and liver at baseline, every 6 weeks during treatment (6 Performed at any time during the week) and EOS (only as required by the prescribed study imaging schedule). At baseline, the method of assessment selected for tumor follow-up should continue consistently throughout the study period.

  G Scans for response evaluation were obtained every 6 weeks during treatment.

  H Reproducibility studies were also performed at EOS visits only as required by the defined study imaging schedule, unless there was other clinical evidence of progression.

  I When there were symptoms of metastasis to the brain, a CT scan of the head or MRI of the brain was performed.

  J A nuclear medicine bone scan was performed at baseline for any patient with clinical symptoms that could have metastasized to bone. For all areas identified as metastatic potential in the bone scan (since this is not definitive), simple film X-rays were then performed to verify that they were actually metastasized. These definitive X-ray studies were performed only at baseline and did not need to be repeated in subsequent bone scans. Bone scans were repeated every 12 weeks and when an objective response was first confirmed or first confirmed.

  KBSA was calculated at baseline and recalculated when body weight changed more than 10% from baseline.

  L Within one week before the first day of each cycle or the first day of each cycle.

  M Within one week before the first day of each cycle or the first day of each cycle. The onset of peripheral neuropathy was reported by the investigator as AE or SAE according to the protocol.

  N Post-study follow-up provided patient survival. Telephone follow-up was conducted once a month for 6 months and every 3 months for the next 12 months (18 months total follow-up). For patients who have not progressed since study initiation, progression-free survival follow-up was performed every 6 weeks by repeating the study required for tumor imaging. When bone scans were used to confirm non-target lesions, they were performed every 12 weeks.

Inclusion Criteria / Exclusion Criteria Patients were eligible for inclusion in this study only if all of the following criteria were met: 1) Stage IIIB or IV NSCLC was established histologically or cytologically; 2) Male or non-pregnant, breast-feeding woman, age ≧ 18 years (if the female patient is likely to become pregnant as evidenced by regular menstrual periods, the female patient will receive the first dose of study drug Within 72 hours, a negative serum pregnancy test (βhCG) must be confirmed and, if sexually active, the patient must agree to the use of contraception as deemed appropriate and appropriate by the investigator 3) No other currently active malignant tumors; 4) Measurable disease identified on radiograph (of at least one measurable lesion identified on radiograph) 5) Patients must not have received prior chemotherapy for the treatment of metastatic disease (adjuvant chemotherapy that enabled the provision of cytotoxic chemotherapy is the start of this study 12) Completed 6 months ago); 6)> 12 weeks expected to survive; 7) ECOG functional status 0 or 1; 8) Patient had the following blood cell counts at baseline: a) ANC ≧ 1. 5 × 10 9 cells / L; b) Platelets ≧ 100 × 10 9 cells / L; and c) Hgb ≧ 9 g / dL; and 9) Patients had the following blood chemistry levels at baseline: a) AST (SGOT), ALT (SGPT) ≦ 2.5 × upper limit of normal range (ULN) or ≦ 5.0 × ULN (for liver metastases); b) total bilirubin ≦ ULN, and c) creatinine ≦ 1.5 mg / DL

  Patients were ineligible for inclusion in this study if any of the following criteria were applied: 1) Evidence of active metastasis to the brain, including buffy coat involvement (treated, stable, for at least 1 month) Evidence of previous brain metastases was accepted only if no therapy was given); 2) The only evidence of disease was not measurable; 3) Patients were grade 2, 3 or 4 (by CTCAE) 4) The patient had been receiving radiation therapy in the last 4 weeks, except when receiving only non-target lesions (the clear progression of the lesions after irradiation was completed) 5) Patient had clinically significant complications; 6) Patient was treated with any study drug within 4 weeks in advance 7) The patient has not received any of the study drugs. 8) significant medical care related to any of the major organ systems that the investigator thinks is not safe for the patient to give an experimental investigational drug; Or 9) The patient was enrolled in any other clinical protocol or trial related to the administration of experimental therapy and / or therapeutic devices.

Dosage and Administration NSCLC patients were randomized to one of two treatment arms. Treatment arm A was assigned a dose of Nab-paclitaxel / carboplatin and treatment arm B was assigned a dose of Taxol / carboplatin. There were approximately 525 intent-to-treat (ITT) patients / arms.

  Nab-paclitaxel or Taxol® was administered only in combination with carboplatin in this study. That is, no other additional chemotherapeutic drugs were administered with the study drug. While enrolling in this study, the patient was unable to participate in any other clinical protocol or trial related to the administration of experimental therapy and / or the use of clinical trial medical devices with therapeutic intent.

  Supportive therapies such as antiemetics and analgesics and erythropoietin may be administered. Simultaneous treatment with bisphosphonate was observed. G-CSF was administered according to the guidelines described herein.

  Patients were able to continue treatment in the absence of progressive disease and unacceptable toxicity as long as their treating physician felt that implementation was the best benefit for the patient. In general, given sufficient tolerability of the regimen, patients are encouraged to receive at least 6 cycles of treatment for full assessment of the treatment regimen. Patients who stopped treatment before the onset of progressive disease were followed without further treatment until the progressive disease was confirmed or the treating physician felt the need for additional treatment.

Treatment arm A (Nab-paclitaxel / carboplatin)
During the treatment phase, patients were randomized to this arm and without any steroid premedication and G-CSF prophylaxis (unless otherwise modified herein) Nab-paclitaxel 100 mg / m 2 . Dosing was received intravenously once a week (on days 1, 8 and 15 of each cycle) for approximately 30 minutes, then AUC = 6 carboplatin was administered on day 1 of each cycle and repeated every 3 weeks. . Carboplatin was infused intravenously over 30-60 minutes after Nab-paclitaxel infusion.

Up to 2 dose reductions were observed from the original dose: a) Initial dose reduction: Nab-paclitaxel reduced to 75 mg / m 2 and carboplatin reduced to AUC4.5 (25% reduction), b) 2nd time Dose reduction: Nab-paclitaxel was reduced to 50 mg / m 2 and carboplatin was reduced to AUC 3.0 (50% reduction).

The dose of Nab-paclitaxel was at the start of the study or on the day of the cycle until the absolute neutrophil count returned to ≧ 1.5 × 10 9 cells / L and the platelet count returned to ≧ 100 × 10 9 cells / L. Not administered in the eye. For each subsequent weekly dose of Nab-paclitaxel, patients had ANC ≧ 0.5 × 10 9 cells / L and platelets> 50 × 10 9 cells / L. If ANC and platelets were not sufficient for the week's treatment, the dose was withheld, provided that ANC was ≧ 0.5 × 10 9 cells / L and platelets> 50 × 10 9 cells / L. Resumed the following week. Subsequent doses were reduced only if the following criteria were met: Nab-paclitaxel was not administered if liver function parameters were outside the range established for enrollment in this study.

Treatment arm B (Taxol / carboplatin)
During the treatment phase, patients were randomized to this arm and received standard Taxol® 200 mg / m 2 intravenously over 3 hours using standard premedication followed by AUC = 6 carboplatin. Administered and repeated every 3 weeks (both drugs were given on the first day of each cycle). Carboplatin was infused by IV over 30-60 minutes.

Up to two dose reductions were observed from the original dose: a) Initial dose reduction: Taxol® reduced to 150 mg / m 2 and carboplatin to AUC4.5 (25% reduction), b) Second dose reduction: Taxol® was reduced to 100 mg / m 2 and carboplatin was reduced to AUC 3.0 (50% reduction).

Taxol® and carboplatin are administered at the beginning of each cycle until the absolute neutrophil count returns to ≧ 1.5 × 10 9 cells / L and the platelet count returns to> 100 × 10 9 cells / L. There wasn't. Neither drug was administered at the start of the cycle if liver function parameters were outside the range established for enrollment in this study.

Nab-paclitaxel Each single-use 50 mL vial contained 100 mg paclitaxel and human albumin (HA) as a stabilizer. Each Nab-paclitaxel vial was reconstituted using a 50 or 60 cc sterile syringe by injecting 20 mL of 0.9% sodium chloride injection or equivalent into each vial for a period of 1 minute or longer (5 mg / ML suspension). The use of in-line filters was generally not necessary, but when used, in-line filters with pore sizes <15 microns (15 μm) were not used.

Taxol
Please refer to the taxol® package insert (current version of prescription information is provided in the study manual) for explanation and prescription. Taxol® (paclitaxel) in 0.9% sodium chloride injection, USP; 5% dextrose injection, USP; 5% dextrose and 0.9% sodium chloride injection, USP; or Ringer's injection Dilute with 5% dextrose to a final concentration of 0.3 to 1.2 mg / mL. Taxol® was administered through an in-line filter with a microporous membrane of 0.22 microns or less.

Carboplatin The chemical name of carboplatin is cis-diamine (cyclobutane-1,1-dicarboxylate-O, O ′) platinum (II). The carboplatin lyophilized powder was reconstituted for IV injection using the appropriate diluent and volume indicated in the package insert. Carboplatin dosing was based on the Calvert formula: carboplatin dose (mg) = (target AUC) × (GFR + 25). For the purposes of this protocol, GFR is considered equivalent to creatinine clearance (calculated by the method of Cockcroft and Gault, 1976). For calculation of carboplatin dose (total mg, not mg / m 2 ): mg of carboplatin = (6) × (CrCl + 25). For obese patients defined as having a body mass index (BMI)> 30 kg / m 2 , kilograms of lean body mass are used instead of actual body weight in the above formula for calculating creatinine clearance.

Dose correction (all arms)
Dose Drop-out Rules-Day 1 dose skipped: If the dose was withheld or skipped, the dose was given on the first day of the next cycle, where the first dose was actually the patient It was considered that it did not start until the day of administration (ie, D1-D8-D15, X-D1-D8-D15, etc.). The dose on day 8 was skipped: the cycle was continued as per protocol without giving one dose (ie D1-D8-D15, D1-X-D15, D1-D8-D15, etc.). If number and chemistry were acceptable, day 15 was administered as per cycle calendar. The dose on day 15 was skipped: the cycle was continued as per the protocol without giving one dose (ie D1-D8-D15, D1-D8-X, D1-D8-D15, etc.). If number and chemistry were acceptable, day 1 was administered as per cycle calendar.

  Hematologic toxicity-Study drug was administered only when liver function was within parameters established in eligibility criteria. Taxane hepatotoxicity can occur, but it was rare. Thus, liver dysfunction that patients develop during the study facilitates evaluation to determine the cause, including progressive metastatic disease and the possibility of liver toxicity from concomitant medications. The following table provided guidelines for practicing dose reduction and growth factor treatment for hematologic toxicity for both study arms:

* See NCI CTCAE Scale for definition of Grade 3 and Grade 4 events ** Up to 7 days after scheduled first day dose for next cycle.

  Administration of colony-stimulating factor—The colony-stimulating factor can be given according to institutional guidelines for the treatment of infections associated with neutropenic fever or neutropenia.

  Hypersensitivity reactions-life-threatening symptoms such as flushing, skin reactions, dyspnea, hypotension or tachycardia may require temporary discontinuation of the infusion. However, severe reactions such as hypotension that requires treatment, dyspnea that requires bronchodilators, angioedema, or systemic urticaria require immediate discontinuation of study drug administration and active symptomatic treatment. Patients who developed a severe hypersensitivity response to any study drug were not challenged again. Treatment with the remaining drug alone was continued.

  Dose reduction for non-hematological toxicity-Table 3 provided guidelines for dose reduction for non-hematological toxicity.

* This decision depended on the type of non-hematological toxicity seen, and this process was the most medically reasonable in the investigator's judgment.

  Peripheral neuropathy—treatment was withheld in patients who experienced ≧ grade 3 peripheral neuropathy. After peripheral neuropathy improved to ≦ grade 1, treatment could be resumed at the next lower dose level in its next cycle (see dose reduction above). Time to resolution to grade ≦ 1 was the adverse event period used for reporting adverse events.

  Skin Toxicity—Patients who developed grade 2 or 3 skin toxicity reduced their dose by one dose level. Treatment was discontinued if patients continued to experience these responses despite dose reductions. Patients who developed grade 4 skin toxicity discontinued treatment.

  Gastrointestinal toxicity—If grade 3 mucositis or diarrhea developed, the study drug was withheld until resolution to ≦ grade 1 and then resumed at the next lower dose level (see dose reduction). Patients who developed grade 4 mucositis or diarrhea discontinued treatment.

  Other toxicity-If toxicity was ≤ Grade 2, the toxicity was treated symptomatically (if possible) and the patient was retreated without dose reduction. If toxicity is ≧ grade 3, withhold until treatment resolves to grade 0, 1, 2, or baseline (if baseline is higher than grade 1), then medically appropriate Resume at lower dose levels (see dose reduction). Recurrence of grade 3 or 4 toxicity after a 2 dose reduction required discontinuation of treatment.

  Dose delay—In patients whose next treatment was delayed ≧ 3 weeks due to sustained toxicity, the next dose was reduced by one dose level.

  Study discontinuation-After adverse doses that required a dose reduction recurred after the dose was reduced twice, treatment was generally discontinued at the investigator's discretion (risk of recurrent toxicity Unless there is evidence of benefit to the patient over and over gender).

Efficacy endpoint The primary efficacy endpoint was the percentage of patients who achieved an objectively established complete or partial response based on a blinded radiological review using the RECIST response guidelines. Important secondary efficacy endpoints are: a) Progressive survival (PFS); b) Patient survival; c) Patients with stable disease of ≧ 16 weeks or who have a complete or partial response It included the percentage (ie, disease control rate); d) duration of response in responding patients; and e) correlation of efficacy results with SPARC and other molecular biomarkers.

  Tumors were evaluated in this study by imaging studies every 6 weeks during therapy (at any time during week 6). For patients who did not progress by the end of treatment, imaging iterations were performed every 6 weeks until tumor progression was confirmed. Secondary analysis included progression-free survival, duration of response in responding patients, disease control rate and patient survival. Safety and tolerability were monitored through reports of incidences of adverse and serious adverse events, laboratory abnormalities, and study drug dose corrections, dose interruptions and / or premature discontinuations . A patient was considered a responder if he achieved an objective complete or partial response according to the RECIST guidelines. We did not replace patients who completed the study early or were randomized but not treated.

Measurable and non-measurable lesions The definition of measurable lesions at baseline depended on the technical elements of the imaging study used to evaluate the patients. Imaging parameter recommendations were based on American College of Radiology (ACR) Practice Guidelines and Technical Standards. Proposals for correction of measurable lesion size at baseline to a reconstruction interval of 2 (2) times the baseline / screening study were consistent with the RECIST definition for measurable lesions. When conventional scans are performed at reconstruction intervals of tens (10) mm or less, the longest diameter (LD) of ≧ 20 (20) mm in at least one (1) dimension is accurately measured by conventional techniques. The resulting lesion was defined as a measurable lesion. A lesion whose longest diameter (LD) can be accurately measured in at least one (1) dimension has a reconstruction interval (RI) twice (2) times that of a spiral CT scan. The minimum size of measurable lesion was 10 (10) mm. The definition of target disease was not changed and was determined based on a baseline scan.

  All other lesions that did not meet the criteria for measurable disease as described above and other lesions that were not truly measurable were considered unmeasurable.

Response of target and non-target lesions Response at each time point was assessed as a combination of target and non-target responses and the presence of new lesions.

  Up to ten (10) target lesions, up to five (5) locations / organs were selected for measurement over the course of the study. The distribution of these target lesions represented the subject's overall disease. Target lesions were not selected from previously irradiated areas, except where the lesions had confirmed progression. Target lesions were measurable at baseline. Measurements were taken and recorded in one dimension for any target lesion at any time. The longest diameter of each target lesion was measured and recorded. The longest diameters of the target lesions were summed to obtain the sum of longest diameters (SLD). Baseline SLD was used as a reference to further characterize the objective tumor response of the target lesion. For the determination of progressive disease, the lowest value of SLD for the target lesion was used as a reference.

  For cases where no target lesion was identified, tumor assessment for progression was performed based on the assessment of non-target lesions or the development of new lesions. Response (PR or CR) and SD were not assessed in subjects where the target lesion was not identified at baseline.

  The following conventions were applied to the selection of target lesions in patients who had previously received radiation therapy: a) Previous axillary irradiation (ie, the terms “axillary”, “axillary” or other related terms) Yes) was not excluded in selecting measurable lesions in the chest wall or chest as the target lesion; b) previous radiation history associated with the previous breast (ie, the term “breast”) ) Or chest wall irradiation (ie, previous radiation history associated with the term “chest wall” or other related term (s)), in selecting a chest wall lesion as a target disease for a chest wall lesion on the same side as the chest wall irradiation site C) Adjacent structures unless previous bone irradiation (eg, spine, ribs, pelvis, femur, etc.) reveals signs of radiation damage (eg, scarring) Did not exclude in the selection of measurable lesions in; and d) if the lesions became new after irradiation was completed by previous soft tissue irradiation (eg irradiation on the clavicle, internal chest lymph node, etc.) Excluded in the selection of measurable disease at the irradiated site.

  All sites of disease present at baseline that were not classified as target lesions were classified as non-target lesions. Each non-target lesion was assessed qualitatively at subsequent time points. Examples of non-target lesions are: a) all bone lesions, regardless of the modality used in their evaluation; b) puffy coat disease; c) skin or lung lymphangitis; d) cystic lesions; Irradiated lesions not shown; f) measurable lesions above a maximum of tens; g) small and numerous lesion groups; and h) pleural effusion / endocardial effusion / ascites.

  Clear new lesions were those that did not exist at baseline. At each time point, the presence of a new lesion was determined. A new multifocal or miliary disease of any size was considered a new lesion. In anatomical sites that were not scanned at baseline, lesions encountered (after baseline) were considered new lesions and represented as progressive disease. Lesions that were present and subsequently resolved and then recurred were considered new lesions and represented as progressive disease.

Response Response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Therase P.M. Et al., J Natl Cancer Inst. 2000, 92: 205-216. This study used RECIST guidelines adjusted based on current medical practice. The blinded radiological review authorization performed by Icon Medical Imaging sets out the main points of revision to the original RECIST guidelines.

  Anti-tumor response was defined as the percentage of patients who achieved an objectively established response (complete response or partial response). Disease control rates (SD for at least 16 weeks or established CR or PR) were further reported. The primary efficacy endpoint was the percentage of patients who achieved an objectively established complete or partial response based on a blinded radiological assessment of response. The superiority of Nab-paclitaxel / carboplatin over Taxol / carboplatin was established when the lower limit of 95.1% CI of pA / pT was> 1.0. In addition to the response rate (pA / pT) ratio and its 95.1% CI, the following is expressed for each treatment regimen: sample size, overall response rate and 95% CI of response rate. Response rate treatment regimen comparisons were tested using the chi-square test.

  The percentage change in SLD was evaluated by the following formula: 1) When determining complete or partial response: ((post-treatment value−baseline value) / baseline value) × 100 and 2) determining advanced disease When: (value after treatment-lowest value from start of treatment) / (lowest value from start of treatment) x 100.

  The following definitions were used to assess response based on target lesions at each time point after baseline: complete response (CR): disappearance of all target lesions. Partial response (PR): A reduction of at least 30% in the SLD of the target lesion with reference to the baseline SLD. Disease Stability (SD): With reference to the lowest SLD from the start of treatment, target lesions are not sufficiently reduced to be PR and insufficient to be PD. Disease progression (PD): Reference to the lowest SLD recorded from the start of treatment, at least a 20% increase in the SLD of the target lesion, or the presence of one or more new lesions. Unevaluable (UE): The target lesion was present at baseline but could not be measured or evaluated, so the status of that particular tumor at the time in question cannot be determined. If the SLD is indeterminate at some point and the PD rules cannot be applied, the CR, PR, or SD response cannot be assigned for that point, and the response at that point is UE. Not applicable (NA): No target lesion was identified at baseline. Patients whose target lesions were not identified at baseline could not be evaluated for response. These patients were only evaluated for progression. Not performed (ND): The scan was not performed at this time and the target lesion was not evaluated.

  Each non-target lesion was assessed qualitatively at each time point. The response of each lesion at each time point was evaluated against baseline status. Progress was assessed against the minimum size of non-target lesions. The overall non-target lesion response for each time point was evaluated as the worst case of non-target lesion for that particular time point. When non-target lesions were classified as UE / ND, the non-target response was UE / ND unless progression was identified in available non-target lesions. Response assessment was defined as follows: complete response (CR): disappearance of all non-target lesions. Disease stability (SD): Remaining one or more non-target lesions that are not CR or PD. Disease progression (PD): “Clear progression” of existing non-target lesion (s) or the appearance of one or more new lesions was considered disease progression. If the PD for a subject is assessed at a point in time based solely on the progression of non-target lesion (s), then additional criteria are required to be met. In this case, the lesion (s) for which the PD was evaluated must be evaluated retroactively from the baseline (or lowest) and compared to the time point in question. If, at the time of progression, the SLD of the lesion (s) increases by 20% or more and the lesion (s) is measured to be 10 mm or more at the longest diameter (LD), then the non-target lesion (s) PD) was evaluated. If the non-target lesion (s) did not meet the above quantitative criteria, the non-target lesion (s) were not evaluated as advanced. For pleural fluid, ascites, endocardial fluid leaching and other bodily fluid collections, if the increase in bodily fluid is estimated to have exceeded 500 cc and is not due to a benign cause (identified on radiograph), progression Were evaluated in subjects who were otherwise stable or responded. Unevaluable (UE): Any target lesion was present at baseline but could not be measured or evaluated, so the status of that particular tumor at the time in question cannot be determined. Not applicable (NA): No non-target lesions were identified at baseline. Not performed (ND): At this time, no scans were performed to evaluate non-target lesions.

  Disease control rates (SD ≧ 16 weeks, or established CR or PR) were analyzed in the same manner as objective responses.

Progression-free survival A final analysis for PFS was performed once on 70% of patients with disease progression or death (any cause) event. This is equivalent to 735 events, providing 85% power, a bilateral type I error of 0.049, and a 0.80 Nab-paclitaxel / carboplatin to Taxol / carboplatin hazard ratio (HRA / T) was detected.

  PFS was analyzed using the Kaplan-Meier method. PFS is defined as the time from the day of randomization to the onset of disease progression or death (any cause), whichever comes first, and is a radiological review of blinded response. Based on evaluation. The PFS for patients who achieved an objectively defined complete or partial response represented the duration of response.

  Patients who had no disease progression or died were censored at the last known time when the patient had no progression. In the event that palliative radiation therapy or surgery occurred at the lesion site, the patient was censored at the last assessment without confirmed progression, prior to the date of radiation therapy or surgery. In follow-up, before progression was confirmed, patients who started a new anticancer therapy (other than radiation therapy) were censored at the last evaluation to confirm that the patient had no progression.

  The frequency of these off-scheduled assessments was expressed for each treatment regimen to assess the impact of the PFS response assessment that was not performed at the scheduled periodic assessment time. . In addition, patients who have events and censorship that occurred at times other than the scheduled periodic assessment have PFS times based on the date of the next scheduled periodic assessment rather than the actual unplanned date. A definite sensitivity analysis was performed. The frequency of skipped response evaluations was expressed in a treatment regimen in order to evaluate the impact of the skipped response evaluation before a visit in which disease progression was confirmed. In addition, two deterministic sensitivity analyzes were performed. In the first susceptibility analysis, these patients were censored at the last visit where the patient was confirmed to have no progression. In a second sensitivity analysis, these patients were considered to have progressed at the time they skipped the response assessment.

  The hazard ratio of Nab-paclitaxel / carboplatin to Taxol / carboplatin (HRA / T) and its 95.1% CI for PFS were evaluated. For each treatment regimen, the following were further evaluated: 95% CI for sample size, number and percentage of patients with disease progression or death, median PFS and median PFS. PFS Kaplan-Meier curves were evaluated for each treatment regimen, and differences in the curves were tested using a log rank test.

Patient Survival A final analysis on patient survival was performed once on 70% of the patients who died. This is equivalent to 735 deaths, provides 85% power, has a bilateral type 1 error of 0.049, and a 0.80 Nab-paclitaxel / carboplatin to Taxol / carboplatin hazard ratio ( HRA / T) was detected. Patient survival was defined as the time from the day of randomization to the patient's death (for any cause). Patient survival was analyzed in a manner similar to PFS.

Safety / Tolerability Endpoints Safety / tolerability endpoints include the incidence of AEs and SAEs occurring during treatment, laboratory abnormalities and study drug dose corrections, dose interruptions and / or premature withdrawal The incidence of patients who experienced

  AEs that occurred during the study were referred to The The NCI Common Termination Criteria for Adverse Events v3.0 (CTCAE) (http://cept.cancer.gov/reporting/ctc.html) if appropriate. Rated according to. AEs not included in the toxicity scale were designated as grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, and grade 5 = death. AEs that were determined to be potentially irrelevant, probable or apparently definitively not related to the study drug did not require further evaluation but were recorded. The drug under study could be interrupted for AE at the investigator's discretion. Patients in need of toxicity management were assessed and at least once a week as indicated by the severity of the event.

According to the NCI CTCAE system of adverse event rating, grade 3 or 4 test values were listed as “severe” or “life threatening”. For example, a neutrophil count <500 / mm 3 meets laboratory standards of grade 4 (“life threatening”). This statement was not always synonymous with the assessment of AE's “serious” criteria of “life threatening”. Definitions for AE and SAE are provided herein.

Because AE is considered serious by the “life threatening” criteria, it is medically judged as possessing “immediate risk of death from an event” rather than from the theoretical possibility of a life threatening result. It was. In cases of neutrophil count <500 / mm 3, AE is taken as AE neutropenia grade 4, this by investigators was determined to represent the event life-threatening immediate patient Except in some cases, it was not automatically considered an SAE. Specifically, uncomplicated grade 4 neutropenia was not reported as SAE. Neutropenia associated with fever, infection, or hospitalization has been reported as SAE.

  Differences between Nab-paclitaxel / carboplatin and Taxol / carboplatin were compared using the Cochran-Mantel-Haenszel test.

  Patients in the treatment population were followed for the onset of AEs throughout the study drug start and end of the study or 30 days after the end of treatment, whichever is longer. Only patients that are clearly confirmed not to receive study drug may be excluded from the treatment population.

  Peripheral neuropathy (PN) (sensory or motor) was reported by grade according to NCI CTCAE. If the PN grade changes (i.e. increases or decreases), the existing AE stop date must be entered and the new AE start date reflecting the new grade should be entered.

Pharmacokinetic endpoints PK measurements of Nab-paclitaxel were randomized and given Nab-paclitaxel / carboplatin at approximately 0.25, 3.5 and 24 hours after the end of infusion, Russia, Ukraine , Obtained for US and Canadian patients (approximately 100 patients). Pharmacokinetic parameters are: maximum plasma drug concentration (C max ), area under the curve of plasma concentration versus time (AUC and AUC inf ), half-life of the apparent terminal portion of the concentration versus time curve (T 1/2 ), Systemic clearance (CL) and volume of distribution (V z ).

  PK parameters were determined using a combination of pharmacokinetic (PK) sparse sampling methods and three-compartment model analysis. AUC is an important indicator of drug availability or the total amount of metabolites present.

  To assess the relationship between drug exposure and safety, the correlation between minimum ANC and PK parameter estimates (eg, absolute AUCinf) was assessed using linear regression analysis with effects on PK parameters in the model. . If these data were abnormally distributed, conversion of the lowest ANC data was considered. To assess the relationship between drug exposure and efficacy, the correlation between objectively established response (based on blinded radiological review) and PK parameter estimation was calculated as the effect on PK parameters in the model. Evaluation was made using the logistic regression analysis used. In order to evaluate the relationship between drug exposure and biomarkers, the correlation between each biomarker and PK parameter estimation was analyzed using a binary outcome model for biomarkers and logistic regression using effects on PK parameters. The analysis was used to evaluate and in a model for biomarkers with continuous values, was evaluated using linear regression analysis with effects on PK parameters.

Laboratory evaluation Hematology parameters-To investigate the maximum degree of myelosuppression, CTCAE grades for WBC, ANC, platelet count and hemoglobin concentration, for each treatment regimen, with the most severe grade for the first cycle of therapy, and Summarized at the most severe grade at any time during therapy, examination of treatment regimen differences was performed using the CMH test. The incidence of patients with grade 3 or 4 CTCAE hematology that occurred after the first dose of study drug was expressed for each group. Data were given for patients with grade 3 or 4 hematology values.

  Clinical chemistry-Liver and kidney function was summarized using CTCAE for ALT, AST, total bilirubin and creatinine. The number and percentage of patients with each CTCAE grade is summarized for each treatment regimen, with the most severe grade for the first cycle of therapy, and the most severe grade at any time during therapy, and the difference in treatment regimen The test was performed using the CMH test. The incidence of patients with grade 3 or 4 CTCAE chemistry that occurred after the first dose of study drug was expressed for each group. Data for patients with grade 3 or 4 chemical values were listed.

Evaluation of molecular biomarkers Tumor biomarkers (mRNA and DNA) were studied to assess prognostic utility in identifying responders and non-responders in both treatment arms. Molecular biomarkers were evaluated on paraffin-embedded (PE) tumor tissue in patient archives enrolled in clinical trials. Blood samples for evaluation of molecular biomarkers were collected within 2 weeks prior to the start of treatment, and then every other cycle (such as cycle 1, 5, 7 day 1). If the patient participates in both pharmacokinetic sampling and optional biomarker blood collection, the withdrawal of baseline blood for the biomarker is reduced to 1 day to reduce the amount of blood drawn with each venipuncture. Conducted at least 2 days before eyes. Approximately 25 mL of blood was collected at each sampling point for molecular biomarker evaluation.

  These biomarkers include both RNA and DNA analysis performed using a PCR-based quantitative assay. With respect to DNA biomarkers, single nucleotide polymorphism (SNP) loss of heterozygosity (LOH), Kras mutations and methylation of tumor-associated gene promoter regions were examined for both tumor tissue and blood. Expression of molecular biomarkers such as SPARC in PE tumor tissue is assessed for mRNA expression and specific epigenetic (promoter gene methylation) status and its potential clinicopathology associated with treatment with Nab-paclitaxel The usefulness was determined. The objective was to evaluate specific tumor associated genes for upregulation and downregulation, and to identify specific gene expression patterns or specific biomarkers associated with treatment response and disease outcome. In addition, PE tissue sections were obtained from immunohistochemistry (IHC) for assessing SPARC and tumor biopsies for validation of molecular tumor biomarkers. Tissues were taken from both randomized arms of the clinical laboratory. Tumor tissue that was available from the biopsy was used. No additional procedures shall be performed for the purpose of obtaining tumor tissue for molecular biomarker analysis.

  In addition, blood biomarkers [circulating tumor cells (CTC) and circulating DNA (cDNA)] showing prognostic utility were assayed in patient monitoring during treatment. These assays can provide an alternative approach to better predict metastatic disease recurrence, disease response, and help in disease management for lung cancer patients. For testing of these biomarkers, patients will be at baseline and on the first day of every other cycle, followed by normal sampling time for blood count and chemistry (see schedule of events). It was required to provide an additional volume of blood (approximately 25 mL).

  Tumor samples were collected from patients treated in this study and preliminary data were obtained on the possible correlation between SPARC expression and response to combination therapy with Nab-paclitaxel / carboplatin or Taxol / carboplatin . Tumor samples were submitted to the central laboratory for SPARC analysis when tumor samples from patients treated in this study were available. Samples were blinded to treatment assignment and response to treatment received by the patient.

  The correlation between SPARC and other molecular biomarkers and efficacy results was analyzed. The following analysis was performed for each treatment regimen. Descriptive statistics were used to summarize biomarkers for responders versus non-responders. Continuous measurements were taken as sample size, average, median, S.P. D. Summarized by minimum and maximum values. Classification measures were summarized by the number and percentage of patients in each category. In order to assess the relationship between objective tumor response and biomarkers, logistic regression analysis was performed using the effect on biomarkers in the model. The relationship with disease management was analyzed in a similar manner. To assess the relationship between PFS and biomarkers, Cox regression analysis was used with effects on biomarkers in the model. In addition, for SPARC and other biomarkers with binary measurements, PFS was summarized by median PFS time (including 95% CI) and hazard ratio (including 95% CI) for each biomarker category. Kaplan-Meier curves for PFS were represented for each biomarker category using a chart, and differences in the curves were examined using a log rank test.

Results Baseline and histological features were well balanced in the two arms. The dose intensity of paclitaxel was higher in the Nab-paclitaxel / carboplatin arm than in the Taxol / carboplatin arm (82 vs. 65 mg / m < 2 > / week). The overall response rate (ORR) for Nab-paclitaxel / carboplatin was determined by independent radiological review (IRR) (33% vs 25%, P = 0.005) (31% improvement) and investigator review ( 37% vs 30%, P = 0.008) (26% improvement), superior to Taxol / carboplatin. Analysis by histology revealed that Nab-paclitaxel / carboplatin significantly improved ORR compared to Taxol / carboplatin in patients with squamous cell carcinoma (41% vs 24%, P <0.001). , IRR) (67% improvement), Nab-paclitaxel / carboplatin was as effective as Taxol / carboplatin in patients with non-squamous cell carcinoma (ORR 26% vs 25%). Nab-paclitaxel / carboplatin was well tolerated compared to Taxol / carboplatin despite the high cumulative paclitaxel dose delivered without premedication (1442 mg / m 2 vs 1131 mg / m 2 ) And the safety profile was significantly improved.

Nab-paclitaxel / carboplatin significantly improved ORR and safety profile as a first line therapy for advanced NSCLC compared to Taxol / carboplatin. Nab-paclitaxel / carboplatin is particularly active in difficulties to treat a squamous cell carcinoma subset, via the gp60-CAV1 pathway in squamous cell carcinoma cells that abnormally overexpress CAV1. The increase in delivered intratumoral Nab-paclitaxel / carboplatin appears to contribute in part (Yoo et al., Lung Cancer. 2003 42: 195-202).

(Example 2)
Treatment of Lung Cancer This example demonstrates that Abraxane® (Nab-paclitaxel or nab-P) vs. Taxol® in combination with carboplatin in all histological types of advanced non-small cell lung cancer (NSCLC). (P) provides results from Phase 3 clinical studies studying the effectiveness of (nab-PC vs. PC).

Method: Patients with first stage IIIB or IV NSCLC (ECOG 0/1), CAUC6 q3w, and weekly nab-P 100 mg / m 2 (n = 521) or premedication without premedication Randomized to P200 mg / m 2 (n = 531) once every 3 weeks. Primary endpoint: ORR with independent radiological review (IRR).

Results: Baseline and histological features were well balanced. The dose intensity of paclitaxel was higher for nab-PC versus PC (82 vs. 65 mg / m < 2 > / week). nab-PC is an IRR (33% vs 25%, P = 0.005) (31% improvement) (1.313 response rate (RR), 95% CI: 1.082, 1.593), and clinical trials It was superior to PC both by review by the responsible physician (37% vs 30%, P = 0.008) (26% improvement) (1.259RR, CI: 1.060, 1.496). Analysis by histology showed that nab-PC significantly improved ORR compared to PC in patients with squamous cell carcinoma (SQC) (41% vs 24%, P <0.001, IRR). ) (67% improvement) (1.669RR, CI: 1.262, 2.208). In non-SQC patients nab-PC was as effective as PC (ORR 26% vs 25%). nab-PC was well tolerated and significantly improved in safety profile compared to PC despite the high dose of paclitaxel delivered (1338 vs 1100 mg / m 2 ).

Conclusion: nab-PC significantly improved ORR and safety profile as a first line therapy for advanced NSCLC compared to PC. nab-PC is particularly active in the SQC subset, including abnormal CAV1 overexpression in squamous cell carcinoma cells (Yoo 2003) and high intratumoral accumulation of nab-P via the gp60-CAV1 pathway. Will contribute in part.

(Example 3)
Phase I / II clinical trials of Nab-docetaxel in patients with hormone-refractory prostate cancer Clinical studies determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Nab-docetaxel given every 3 weeks The toxicity of Nab-docetaxel was characterized, and the pharmacokinetic parameters for Nab-docetaxel when given on a 3-weekly schedule were determined. The study also evaluated the efficacy of Nab-docetaxel in this patient population.

Treatment Design This phase I study determined the MTD and DLT of Nab-docetaxel administered every 3 weeks. The starting dose of Nab-docetaxel was selected based on nonclinical data and experience with solvent-based docetaxel.

Dose escalation schedule (Nab-docetaxel administered on the first day of every 3 weeks cycle): included dosages are 30, 45, 60, 75, 100, 125, 150, 175 and 200 mg / m 2 there were.

  Three patients were enrolled at each dose level and started at dose level 1. If no DLT was observed, 3 patients were enrolled at the next dose level. When 1 DLT was observed, the dose level was expanded to a maximum of 6 patients. When two DLTs were observed at a given dose level, the MTD was exceeded. The sub-dose level was expanded to a total of 6 patients and <1 of 6 patients experienced DLT at this dose level, which was defined as MTD. All patients at a given dose level completed one cycle of therapy before enrolling the patient at the next dose level. In the Phase II part of the study, up to 35 additional patients were enrolled in the MTD, with a maximum of 41 patients at that dose level (including 6 patients from the Phase I part of the study) ). The maximum total number of patients treated in this study was 77 patients.

Phase II MTD was established at 75 mg / m 2 .

  Patients continued treatment until they experienced progressive disease or unacceptable toxicity, withdrawal of consent, or their physicians no longer felt it was the patient's greatest benefit. Each cohort received one cycle of treatment prior to dose escalation.

  In this study, DLT was treated with any Grade 3 or 4 treatment-related non-hematological toxicity (excluding nausea and vomiting) using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE); Severe grade 3 or 4 nausea or vomiting; grade 4 thrombocytopenia or anemia for any period of time and grade 4 complication-free neutropenia over 7 days (ie, no fever or infection) Defined as Neutropenia with fever or infection was considered a DLT regardless of duration, or any grade 3 hematological toxicity requiring a postponement of treatment beyond 3 weeks was considered a DLT. DLT was determined in cycle 1 for purposes of dose escalation and MTD determination.

  The study consisted of the following phases (see Time and Event Schedule).

  Baseline assessment (imaging scan was performed within 28 days of study drug administration).

  Treatment: Therapy continued in the absence of disease progression (based on PSA assessment, tumor response and radionuclide bone scan) and unacceptable toxicity.

  PSA assessment: Patients had a PSA assessment performed on day 1 of each cycle. Caveolin-1 levels were measured on the first day of each cycle.

  Tumor response assessment: Patients are assessed every 12 weeks for complete response (CR), partial response (PR), disease stability (SD) or disease progression (PD) or at the onset of PSA or onset of new symptoms. The disease progression was evaluated. Tumor response was assessed using the RECIST criteria.

• Pharmacokinetic sampling-Phase I cycle 1 only. The parameters determined included distribution volume, terminal half-life, C max , t max , AUC inf , and plasma clearance.

  • End of study (EOS) assessment: Laboratory and clinical assessments were performed to assess AEs when patients were removed from the study. If not received within the previous 28 days, radiological studies on antitumor response were repeated.

  Adverse event collection and follow-up-Any AEs that developed between the first dose of study drug and 30 days after the last dose of study drug (whichever was later) were collected.

  -Follow-up of disease progression: Patients who did not have progressive disease by EOS assessment will continue to undergo PSA assessment every 3 weeks, and tumor response will be assessed (based on PSA assessment or tumor response) This was carried out every 12 weeks until progression was confirmed.

  Table 4 provides a summary.

A EOS = end of study. When the patient finished the study, the indicated test was conducted. The study on tumor response was repeated only if not done before 28 days.

  Follow-up of BAE and SAE continued for 30 days after the patient discontinued the study drug. Any AE / SAE that began during this period was followed until it stabilized and no longer improved, or until they dissipated. If there is no AE or SAE continuation at the EOS visit, follow-up can be performed by telephone to the patient once a week up to 30 days from the last dose of treatment.

  C Abdominal and pelvic CT or MRI scans were performed until disease progression at baseline and every 12 weeks or at the onset of PSA or onset of new symptoms. Whichever method was chosen at baseline to follow the tumor, it was consistent throughout the study period.

  D Reproducibility studies were also performed at EOS visits unless there was other clinical evidence of progression if not performed before 28 days.

  E A CT scan of the head could be performed if there were gross symptoms of brain metastasis (only if clinically indicated).

  F Baseline examination, physical examination, body weight, Zubrod and peripheral neuropathy assessment (doctors and patients), PSA and caveolin-1 if completed within 72 hours prior to treatment, these assessments are on day 1 of cycle 1 There was no need to repeat.

  GPSA assessments were collected every 3 weeks until disease progression.

  H BSA was calculated at baseline and recalculated only when body weight changed more than 10%.

  Before and after I Nab-docetaxel injection.

  J Completed before the first dose of each cycle.

K study drug, ANC returns to ≧ 1.5 × 10 9/1, platelet return to ≧ 100 × 10 9/1, or any other toxic until dissipated Grade 1, the administration at the beginning of the cycle should not be done.

  L Nab-docetaxel and 5 mg of prednisone orally twice a day (morning and evening) on the first day of each cycle.

  M Before cycle 2 only.

  N Required within 10 days prior to initial dose of study drug.

Inclusion / Exclusion Criteria Patients were eligible for inclusion in this study only if all of the following criteria were met: 1) Patients were histologically or cytologically confirmed for hormonal therapy Must have prostate adenocarcinoma that is clinically refractory and 2) Zubrod functional status 0-1, 3) At enrollment, the patient must have evidence of progressive metastatic disease: a) any Must have either a measurable disease with a level of serum PSA or b) an unmeasurable disease of PSA ≧ 5 ng / ml (having only PSA ≧ 5 ng / ml, Patients with no other radiological evidence were not eligible) 4) Patients must be demonstrated evidence of progressive disease with the latest changes in therapy 5) Within 2 weeks prior to commencement of treatment Decision Maintained testosterone in serum ≦ 50 ng / ml, 6) maintenance of castration (patients who have not undergone surgical orchiectomy will continue drug therapy [eg, gonadotropin releasing hormone analog (GnRH analog)] Maintained castration levels of medium testosterone.Patients given antiandrogens as part of their primary hormone therapy discontinued antiandrogens prior to enrollment and showed disease progression (6 weeks withdrawal for Casodex) ; 4 weeks for flutamide))), 7) Megestrol acetate (Megace®) treatment may continue if the patient is on a constant dose of the drug. If the patient discontinued Megace, the patient showed disease progression due to discontinuation of the drug, 8) age ≧ 18 years, 9) 4 weeks after major surgery, 10) in the previous therapy of metastatic disease Restrictions apply: a) no previous chemotherapy regimen for metastatic disease, b) no more than one previous course of palliative radiation therapy, c) non-chemotherapeutic drugs (eg kinase inhibitors, Up to one previous treatment with an immunotherapeutic agent) was accepted as a treatment for metastatic disease, d) no prior radioisotope therapy with strontium-89, samarium or similar agents As well as e) older than 3 years, accepted previous neoadjuvant or adjuvant chemotherapy regimen, 11) no restrictions on previous hormone therapy, 12) patients All treatments were discontinued for at least 4 weeks prior to study drug administration, 13) Life expectancy was ≧ 3 months, 14) Information indicating that the patient understood the nature of the trial for the proposed treatment 15) Initial laboratory data required: a) WBC ≧ 3,000 / μl, b) ANC ≧ 1,500 / μl, c) Platelet count ≧ 100,000 / μl, d) Creatinine ≦ 1.5 × normal upper limit, e) total bilirubin ≦ normal upper limit (except for patients with Gilbert's disease), f) SGOT (AST) ≦ 1.5 × normal upper limit, and f) SGPT (ALT ) ≦ 1.5 × upper limit of normal, 16) Taxanes are considered teratogenic (for this reason, men whose sexual partner is of gestational age should use sufficient contraception during the study period Agreed ( Hormone control or barrier method)), and 17) in the case of obesity (body weight> 20% of ideal body weight), patients will have adjusted body surface area (BSA) (based on calculated adjusted weight) or It must be treated with a dose calculated using actual BSA.

  Progressive disease in the inclusion criteria was defined as any one of the following (measurable disease, bone scan or PSA progression): 1) measurable disease progression (target from the point of maximum regression) Objective evidence of> 20% increase in the sum of the longest diameter of lesions (LD), or the appearance of one or more new lesions), 2) Bone scan progression (appearance of any of the progressions consisting of: (A) two or more new lesions in a bone scan due to prostate cancer, or (b) an increase in PSA in conjunction with one new lesion in a bone scan due to prostate cancer), or 3) PSA Progression of PSA (≧ 5 ng / mL), stepwise from baseline twice in the presence of radiological evidence of disease, each at least 1 week apart. If less than the PSA level, then additional tests for elevated PSA is required to confirm the progress).

  Patients were ineligible for inclusion in the study if any of the following criteria were applied: 1) Patients cannot be given any other study drug 2) Patients Daily multivitamins, low doses (≦ 400 IU qd) vitamin D, Calcitol (≦ 0.5 mcg qd) and calcium supplements may continue, but all other herbs, alternatives and dietary supplements (ie PC-Spes, Saw Palmetto, St John Wort, etc.) must be discontinued before treatment commences 3) Patients receiving a fixed dose of bisphosphonate (which subsequently develops tumor progression) may continue with this drug Good (but initiation of bisphosphonates can disrupt the interpretation of adverse events, so patients should be Bisphosphonate therapy could not be initiated during the period of 4). 4) Patients with known brain metastases often confused the evaluation of neurological and other adverse events 5) Patients with a history of allergic reactions due to solvent-based docetaxel (Taxotere) were excluded from this clinical trial because they developed possible progressive neurological dysfunction. 6) Congestion Excluded patients with significant cardiovascular disease, including congenital heart failure (New York Heart Association Class III or IV), active angina or recent myocardial infarction (within the last 6 months), 7) non-melanoma skin Patients with “currently active” secondary malignancies other than cancer were not enrolled (patients completed the therapy and relapsed 8) If not considered to be “currently active” malignancies (if considered by their physician) to be less aggressive, 8) but not limited to ongoing or active infection Patients with uncontrolled comorbidities, including symptomatic, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia or psychotic / social conditions that limit the research required, or 9) immunodeficiencies Because of the possibility of a pharmacokinetic interaction with docetaxel in HIV-positive patients receiving combination antiretroviral therapy because the risk of fatal infection increases when treated with myelosuppressive therapy Excluded from this study.

Dosage and administration All patients were treated with Nab-docetaxel IV (60 minutes infusion ± 5 minutes) administered every 3 weeks + 5 mg prednisone orally administered twice daily (morning and evening). Three patient cohorts were given 60, 75, 100, 125, 150, 175 or 200 mg / m 2 of Nab-docetaxel, respectively, as a one hour infusion on the first day of each phase 1 cycle. . The dose of Nab-docetaxel was increased in stages depending on the toxicity profile observed in the previous 3 patient cohorts.

Efficacy endpoint The primary efficacy endpoint was the percentage of patients who achieved a defined prostate specific antigen (PSA) response, and PSA response was defined as either PSA normalization or PSA decline. Normalization of PSA is based on PSA <1.0 ng / ml for patients treated with radiation therapy alone for primary disease and PSA for patients undergoing prostatectomy in two consecutive assessments separated by at least 4 weeks. Defined as undetectable. A decrease in PSA was defined as a decrease in PSA value ≧ 50% from pre-treatment in two consecutive assessments separated by at least 4 weeks. Pretreatment PSA values were measured within 2 weeks prior to the start of therapy.

  Secondary efficacy endpoints are: a) For patients with measurable disease who have achieved an objectively established complete or partial overall tumor response using the RECIST criteria in solid tumors It included percentage, b) time to PSA progression, c) progression-free survival based on tumor response using the RECIST criteria.

PSA Assessment In previous studies, other investigators have shown the prognostic importance of post-therapy decline in PSA. Tahir SA et al., Clin Cancer Res. 2003; 9: 3653-9. Based on this study, the NCI consensus group proposed the following guidelines for the use of post-therapy PSA changes in androgen-independent diseases. Kelly WK et al., J Clin Oncol. 1993; 11: 607-615.

  PSA normalization consists of two consecutive assessments at least 4 weeks apart, with PSA <1.0 ng / ml for patients treated with radiation therapy alone for primary disease and PSA for patients with prostatectomy Defined as undetectable.

  A decrease in PSA was defined as a decrease in PSA value ≧ 50% from pre-treatment with two consecutive assessments separated by at least 4 weeks. Pretreatment PSA values were measured within 2 weeks prior to the start of therapy.

  The progression of PSA was defined as the date of PSA increase that met the criteria for progression (ie not the date of confirmation).

  In patients who achieved a ≧ 50% reduction in PSA, progression is: 1) a 50% increase in PSA above the minimum, and 2) a minimum 5 ng / mL increase in PSA, or up to a pre-treatment PSA value And 3) confirmation by two consecutive PSA elevations separated by at least 2 weeks.

  In patients whose PSA did not decrease by ≧ 50%, progression was 1) a 25% increase in PSA above the pre-treatment or minimum PSA level (whichever is lower), and 2) a minimum of 5 ng / mL PSA And 3) confirmation by two consecutive PSA elevations separated by at least 2 weeks.

  Note: If no confirmation is observed because the patient started new anticancer therapy after the first PSA progression was observed, then the patient is considered to have confirmed PSA progression It was.

Response At baseline, tumor lesions were classified as follows: measurable (lesions that can be accurately measured in at least one dimension [record the longest diameter] but ≥20 mm or spiral CT scan using conventional techniques. ≧ 10 mm) or not measurable (small lesions [all other lesions including longest diameter <20 mm using conventional techniques or <10 mm using spiral CT scan) as well as lesions that are truly unmeasurable).

  All measurable lesions (representative of all related organs) up to a total of 10 lesions with a maximum of 5 lesions / organs were identified, recorded and measured as target lesions at baseline. Target lesions were selected based on their size (those with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinical). The sum of the longest diameters for all target lesions was calculated and reported as the baseline longest diameter sum. The baseline longest diameter sum was used as a reference to characterize objective tumor response.

  All other lesions (or disease sites) were identified as non-target lesions.

  Anti-tumor activity should be assessed according to the RECIST guidelines in patients with measurable and / or non-measurable lesions.

  The following definitions were used to assess the response based on the target lesion at each time point after baseline: complete response (CR): disappearance of all known diseases and absence of new sites or disease-related symptoms (first time Confirmed at least 4 weeks after confirmation). All sites were evaluated including sites that could not be measured, such as leaching or markers. Partial response (PR): The sum of the longest diameters in the target lesion is reduced by at least 30% with reference to the sum of the longest diameters of the baseline (determined at least 4 weeks after initial confirmation) PR was also recorded when all measurable disease had disappeared completely, but there was still an unmeasurable component (ie ascites) and it was not progressing. Disease stability (SD): The target lesion is insufficiently reduced to achieve partial response, and not sufficiently increased to cause disease progression. Disease progression (PD): With reference to the sum of the smallest longest diameters recorded from the start of treatment, the sum of the longest diameters of the target lesions increases by at least 20%, or the appearance of one or more new lesions, or non-target lesions Clear progress.

  Response assessment of non-target lesions was defined as follows: complete response (CR): disappearance of all non-target lesions and normalization of tumor marker levels (confirmed at least 4 weeks after initial confirmation). Disease stability (SD): Remaining one or more non-target lesion (s) and / or maintaining tumor marker levels above the normal range. Disease progression (PD): Appearance of one or more non-target lesions and / or clear progression of existing non-target lesions. Unevaluable (UE): No non-target lesion (s) are confirmed at baseline or from the start of treatment.

Time to PSA progression Time to PSA progression was summarized using the Kaplan-Meier method. PSA progression time was defined as the time from the initial dose of study drug to the onset of PSA progression. Patients who did not have PSA progression at the end of follow-up were censored at their final PSA assessment.

Progression-free survival based on tumor response Progression-free survival was summarized using the Kaplan-Meier method. Progression-free survival was defined as the time from the initial dose of study drug to the onset of disease progression or patient death (for any cause), whichever occurred first. Patients who did not have disease progression or did not die were censored at the last known time when the patient had no progression.

Safety / Tolerability Endpoint The primary safety endpoint was the determination of MTD and DLT for Nab-docetaxel in patients with HRPC. Other secondary safety / tolerability endpoints include the incidence of adverse events (AEs) and serious adverse events (SAEs) caused by treatment, laboratory abnormalities, and the lowest bone marrow during study drug administration Includes the percentage of patients experiencing suppression and dose modification of each study drug, dose discontinuation and / or premature discontinuation.

  The AEs that occurred during the study were referred to The The NCI Common Termination Criteria for Adverse Events v3.0 (CTCAE) (http://cept.cancer.gov/reporting/ctc.html) if appropriate. Rated according to. AEs not included in the toxicity scale were designated as grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, and grade 5 = death. Non-serious AEs that were determined to be possibly unrelated, probably or clearly unrelated to the study drug were recorded, although no further evaluation was required. The drug under study could be interrupted for AE at the investigator's discretion. Patients in need of toxicity management were assessed and at least once a week as indicated by the severity of the event.

According to the NCI CTCAE system of adverse event rating, grade 3 or 4 test values were listed as “severe” or “life threatening”. For example, a neutrophil count <500 / mm 3 meets laboratory standards as grade 4 (“life threatening”). This statement was not always synonymous with the assessment of AE's “serious” criteria of “life threatening”. Definitions for AE and SAE are provided herein.

Because AE is considered serious by the “life threatening” criteria, it is medically judged as possessing “immediate risk of death from an event” rather than from the theoretical possibility of a life threatening result. It was. In cases of neutrophil count <500 / mm 3, AE is taken as AE neutropenia grade 4, this by investigators was determined to represent the event life-threatening immediate patient Except in some cases, it is not automatically considered an SAE. Specifically, no uncomplicated grade 4 neutropenia was reported as SAE. Neutropenia with fever, infection or hospitalization was reported as SAE.

  Patients in the treatment population were followed for the development of AEs throughout the study drug start and end of study, or 30 days after the end of treatment, whichever was longer. Only patients that are clearly confirmed not to receive study drug may be excluded from the treatment population.

Pharmacokinetic Endpoints The pharmacokinetic endpoints are: elimination rate constant, elimination half-life, volume of distribution (V z ), maximum plasma drug concentration (C max ), T max, area under the curve of plasma concentration versus time ( AUC inf ) and plasma clearance.

Laboratory evaluation Hematology parameters-To investigate the maximum degree of myelosuppression, the CTCAE grade for WBC, ANC, platelet count and hemoglobin concentration is the most severe grade for the first treatment cycle and any during therapy Summarized by the most severe grade in time. The incidence of patients with grade 3 or 4 CTCAE hematology that occurred after the first dose of study drug was expressed for each group. Data were given for patients with grade 3 or 4 hematology values.

  Clinical chemistry-Liver and kidney function was summarized using CTCAE for ALT, AST, total bilirubin and creatinine. The number and percentage of patients with each CTCAE grade is summarized for each treatment regimen, with the most severe grade for the first cycle of therapy, and the most severe grade at any time during therapy, and the difference in treatment regimen The test was performed using the CMH test. The incidence of patients with grade 3 or 4 CTCAE chemistry that occurred after the first dose of study drug was expressed for each group. Data for patients with grade 3 or 4 chemical values were listed.

Evaluation of molecular biomarker The expression level of caveolin-1 (Cav1) was evaluated.

Results PSA (prostate specific antigen) response rates were measured using albumin and docetaxel, ie Nab-docetaxel (at a dose of 75 mg / m 2 q3wk), or a nanoparticle composition comprising a combination of Nab-docetaxel and prednisone Measurements were made in 42 treated patients. In 13 patients treated with nab-docetaxel alone, a confirmed PSA response occurred in 3/13 (23%). In 29 patients treated with nab-docetaxel plus prednisone, a confirmed PSA response occurred at 13/29 (45%), almost twice that seen with nab-docetaxel alone. Thus, Nab-based delivery of docetaxel enhances the effect of prednisone on prostate cancer tumors.

Example 4
Phase I study of Nab-paclitaxel and carboplatin and thoracic radiation in patients with locally advanced NSCLC One third of patients with NSCLC exhibit local unresectable disease. Synchronous chemoradiotherapy with weekly paclitaxel (Taxol) and carboplatin has a median survival of about 14 months. Phase I clinical trial started in patients with unresectable stage III NSCLC using weekly Nab-paclitaxel and carboplatin and thoracic radiation therapy to determine safety and tolerability did.

Patients with inoperable stage IIIA or IIIB NSCLC, PS0-1 and FEV1> 800 ml were enrolled in an ascending dose cohort in the weekly modified 3 + 3 design of Nab-paclitaxel. This started at 40 mg / m 2 , increased by 20 mg / m 2 increments, combined with weekly carboplatin (AUC2) 7 weeks, and divided into 33 by either 3D conformal or intensity modulation methods Synchronous chest radiation was performed. Patients received 2 cycles of consolidation with full doses of Nab-paclitaxel (100 mg / m 2 once weekly for 3 weeks) and carboplatin (AUC6, day 1 of each cycle, every 21 days). It was. The DLT (dose limiting toxicity) period is defined as the period of synchronic actinic radiation.

Results Eleven patients were enrolled. Ten patients were treated with two dose levels of Nab-paclitaxel, 40 mg / m 2 (6 patients) and 60 mg / m 2 (4 patients). One patient signed a consent form but subsequently withdrew. Six patients were treated with 40 mg / m 2 and there was no DLT. Four patients were treated with 60 mg / m 2 and had 2 DLTs, radiation dermatitis and esophagitis. Grade 2-3 toxicities during synchronic treatment include neutropenia, neutropenic fever, anemia, thrombocytopenia, malaise, esophagitis, mucositis, nausea, dermatitis, hypoxia And included dehydration. No grade 4 toxicity was seen during the synchronic treatment. Ten patients were evaluable for response, 9 had partial response and 1 had disease stability. Seven patients progressed 3, 5, 6, 7 and 8, 16 and 20 months after enrollment, and 3 patients remained stable for 2, 4 and 28 months. The recommended phase II dose of Nab-paclitaxel once a week is 40 mg / m 2 .

Nab-paclitaxel at 40 mg / m 2 once weekly was safe and well tolerated when used in combination with weekly carboplatin and chest radiation.

  Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor variations and modifications may be practiced. Accordingly, the description and examples should not be construed as limiting the scope of the invention.

Claims (17)

  1. A medicament for treating NSCLC in an individual comprising:
    a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and albumin;
    b) a combination of an effective amount of a platinum-based drug, treatment-out based on the NSCLC is a squamous cell carcinoma, the platinum-based agent is carboplatin, pharmaceutical.
  2.   The medicament according to claim 1, wherein the individual is selected for treatment based on having squamous cell carcinoma.
  3.   The medicament according to claim 1 or 2, wherein the treatment is further based on NSCLC with high levels of caveolin-1 (CAV-1).
  4. Wherein the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin, is 50mg / m 2 ~125mg / m 2 , medicament according to any one of claims 1 to 3.
  5.   The medicament according to any one of claims 1 to 4, wherein the composition comprising nanoparticles comprising paclitaxel and albumin is administered once a week.
  6.   The medicament according to any one of claims 1 to 5, wherein the effective amount of the platinum-based drug is AUC = 2 to AUC = 6.
  7.   The medicament according to any one of claims 1 to 6, characterized in that the platinum-based drug is administered once every three weeks.
  8. The effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin is 100 mg / m 2 once a week, and the effective amount of the platinum-based drug is administered once every 3 weeks. The pharmaceutical according to any one of claims 1 to 4, wherein AUC = 6.
  9.   The medicine according to any one of claims 1 to 8, wherein paclitaxel in the nanoparticles is coated with albumin.
  10.   The medicine according to any one of claims 1 to 9, wherein an average diameter of the nanoparticles in the composition is 200 nm or less.
  11.   11. The medicament according to any one of claims 1 to 10, wherein the NSCLC is stage IIIB NSCLC or stage IV NSCLC.
  12.   The medicament according to any one of claims 1 to 11, characterized in that the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based drug are administered parenterally.
  13.   The medicament according to claim 12, characterized in that the composition comprising nanoparticles comprising paclitaxel and albumin and the platinum-based drug are administered intravenously.
  14. It said individual is a human medicament according to any one of claims 1 to 1 3.
  15. It said individual is at least 70 years of age, medicament according to claim 1 4.
  16. The medicament according to any one of claims 1 to 15 , characterized in that the medicament is administered in combination with a chest radiation treatment.
  17. Wherein the effective amount of the composition comprising nanoparticles comprising paclitaxel and albumin, is 20mg / m 2 ~60mg / m 2 administered once a week, wherein the effective amount of a platinum-based drug, once a week a AUC = 2~AUC = 6 administration, and a synchronic, the chest radiation is 25 to 40 split via the 3D conformal method or intensity modulation method, according to claim 1 6 pharmaceutical .
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